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Gladkauskas T, Cristea I, Mehrasa R, Demoulin JB, Gjertsen BT, Bruland O, Rødahl E, Bredrup C. Temperature as a Key Modulator: Investigating Phosphorylation Patterns of p.Asn666 PDGFRB Variants and Their Role in Downstream Signaling. Hum Mutat 2025; 2025:6664372. [PMID: 40309479 PMCID: PMC12041633 DOI: 10.1155/humu/6664372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 03/27/2025] [Indexed: 05/02/2025]
Abstract
Four different amino acid substitutions have been reported at the p.Asn666 position in platelet-derived growth factor receptor β (PDGFRβ): p.Asn666Lys, p.Asn666Tyr, p.Asn666Ser, and p.Asn666His. All four substitutions result in strikingly different phenotypes, ranging from somatic infantile myofibromatosis in p.Asn666Lys and ocular pterygium-digital keloid dysplasia in p.Asn666Tyr to a severe form of Penttinen syndrome in p.Asn666Ser, while p.Asn666His is associated with a complex phenotype characterized by debilitating hand and foot contractures and facial coarseness. Here, we show that the p.Asn666Lys, p.Asn666Tyr, and p.Asn666His substitutions result in increased total PDGFRβ phosphorylation at 32°C compared to 37°C. All four substitutions exhibit distinct activation patterns of specific PDGFRβ tyrosine residues at both temperatures, indicating a unique activation of each variant. The temperature effect on downstream signaling is present across all substitutions, resulting in substitution-specific downstream signaling at both 37°C and 32°C. This complex interplay of downstream signaling proteins could be important for the clinical manifestations of p.Asn666 PDGFRB variants. Furthermore, variant-specific overactivation of tyrosine residues and downstream signaling at 32°C emphasize the importance of temperature as an environmental factor in the pathogenesis of this diverse group of disorders.
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Affiliation(s)
- Titas Gladkauskas
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Bergen Center for Medical Stem Cell Research, University of Bergen, Bergen, Norway
| | - Ileana Cristea
- Bergen Center for Medical Stem Cell Research, University of Bergen, Bergen, Norway
- Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway
| | - Roya Mehrasa
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | | | - Bjørn Tore Gjertsen
- Department of Internal Medicine, Haukeland University Hospital, Bergen, Norway
| | - Ove Bruland
- Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Eyvind Rødahl
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway
| | - Cecilie Bredrup
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Bergen Center for Medical Stem Cell Research, University of Bergen, Bergen, Norway
- Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway
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2
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Yang D, Huang H, Zeng T, Wang L, Ying C, Chen X, Zhou X, Sun F, Chen Y, Li S, Wang B, Wu S, Xie F, Cen Z, Luo W. Unveiling distinct clinical manifestations of primary familial brain calcifications in Asian and European patients: A study based on 10-year individual-level data. Parkinsonism Relat Disord 2025; 132:107290. [PMID: 39827654 DOI: 10.1016/j.parkreldis.2025.107290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/06/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
BACKGROUND Primary Familial Brain Calcification (PFBC) can manifest clinically with a complex and heterogeneous array of symptoms, including parkinsonism, dysarthria, and cognitive impairment. However, the distinct presentations of PFBC in Asian and European populations remain unclear. METHODS We conducted a systematic search of PubMed for studies involving genetically confirmed PFBC patients. Demographic data, genetic information, radiological examinations, and clinical characteristics were extracted for each case. RESULTS The study included 120 publications and 564 genetically confirmed PFBC patients. Asian and European PFBC populations represented 54 % and 37 % of global patients, respectively. While calcification patterns showed no significant differences between Asian and European PFBC patients, European autosomal dominant PFBC variant carriers were more likely to exhibit clinical symptoms compared to their Asian counterparts (OR = 2.90, 95 % CI 1.55-5.60) and had an earlier estimated age of onset (median age 42 vs 58). CONCLUSION The interaction between regional differences and genetically determined calcification severity may collectively influence PFBC symptom progression. Future research should further explore the potential roles of gene modifiers, ethnic background, socioeconomic and environmental exposure factors underlying regional differences in PFBC progression.
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Affiliation(s)
- Dehao Yang
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Honghao Huang
- Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tian Zeng
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lebo Wang
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Chenxin Ying
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xinhui Chen
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xinbo Zhou
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Fangyue Sun
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yilin Chen
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shengqi Li
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Bo Wang
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Sheng Wu
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Fei Xie
- Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhidong Cen
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Wei Luo
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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Cao C, Luo J, Wang X. Case report: Primary familial brain calcification associated with a rare PDGFRB variant, coexisting with nontraumatic osteonecrosis of the femoral head. Front Neurosci 2024; 18:1381840. [PMID: 38859923 PMCID: PMC11163128 DOI: 10.3389/fnins.2024.1381840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 05/15/2024] [Indexed: 06/12/2024] Open
Abstract
Primary familial brain calcification (PFBC) is a rare genetic neurodegenerative disorder characterized by bilateral calcifications in the brain. PFBC may manifest with a broad spectrum of motor, cognitive, and neuropsychiatric symptoms. Several causal genes have been identified in PFBC, which are inherited as both autosomal dominant and autosomal recessive traits. Herein, we present the case of a Chinese family diagnosed with PFBC. The family members carry a rare heterozygous variant (p. R334Q) in exon 7 of platelet-derived growth factor receptor β (PDGFRB) gene. The platelet-derived growth factor-B/PDGF receptor β (PDGF-B/PDGFRβ) signaling pathway plays a crucial role in pericyte development in various organs and tissues. Notably, this variant uniquely coexists with nontraumatic osteonecrosis of the femoral head. Additionally, we reviewed previous studies on PFBC-causing variants in PDGFRB.
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Affiliation(s)
- Conghui Cao
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, China
| | - Jing Luo
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, China
- Department of Endocrinology and Metabolism, Tieling Central Hospital, Tieling, China
| | - Xiaoli Wang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, China
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Al Ali J, Yang J, Phillips MS, Fink J, Mastrianni J, Seibert K. A case report of a patient with primary familial brain calcification with a PDGFRB genetic variant. Front Neurol 2023; 14:1235909. [PMID: 37780723 PMCID: PMC10538541 DOI: 10.3389/fneur.2023.1235909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 08/30/2023] [Indexed: 10/03/2023] Open
Abstract
Fahr's disease, or primary familial brain calcification (PFBC), is a rare genetic neurologic disease characterized by abnormal calcification of the basal ganglia, subcortical white matter and cerebellum. Common clinical features include parkinsonism, neuropsychiatric symptoms, and cognitive decline. Genes implicated in Fahr's disease include PDGFB, PDGFRB, SLC20A2, XPR1, MYORG, and JAM2. We present the case of a 51-year-old woman who developed subacute cognitive and behavioral changes primarily affecting frontal-subcortical pathways and parkinsonism in association with extensive bilateral calcifications within the basal ganglia, subcortical white matter, and cerebellum on neuroimaging. Relevant family history included a paternal aunt with parkinsonism at age 50. Normal parathyroid hormone and calcium levels in the patient's serum ruled out hypoparathyroidism or pseudohypoparathyroidism as causes for the intracranial calcifications. Genetic panel sequencing revealed a variant of unknown significance in the PDGFRB gene resulting in a p.Arg919Gln substitution in the tyrosine kinase domain of PDGFRB protein. To our knowledge this is the first report of a p.Arg919Gln variant in the PDGFRB gene associated with PFBC. Although co-segregation studies were not possible in this family, the location of the variant is within the tyrosine kinase domain of PDGFRB and pathogenicity calculators predict it is likely to be pathogenic. This report adds to the list of genetic variants that warrant functional analysis and could underlie the development of PFBC, which may help to further our understanding of its pathogenesis and the development of targeted therapies for this disorder.
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Affiliation(s)
- Jamal Al Ali
- Department of Neurology, University of Chicago, Chicago, IL, United States
| | - Jessica Yang
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States
| | - Matthew S. Phillips
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States
| | - Joseph Fink
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States
| | - James Mastrianni
- Department of Neurology, University of Chicago, Chicago, IL, United States
| | - Kaitlin Seibert
- Department of Neurology, University of Chicago, Chicago, IL, United States
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Chen SY, Ho CJ, Lu YT, Lin CH, Lan MY, Tsai MH. The Genetics of Primary Familial Brain Calcification: A Literature Review. Int J Mol Sci 2023; 24:10886. [PMID: 37446066 DOI: 10.3390/ijms241310886] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Primary familial brain calcification (PFBC), also known as Fahr's disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among the diverse clinical phenotypes, the most common manifestations are movement disorders, cognitive deficits, and psychiatric disturbances. Although patients with PFBC always exhibit brain calcification, nearly one-third of cases remain clinically asymptomatic. Due to advances in the genetics of PFBC, the diagnostic criteria of PFBC may need to be modified. Hitherto, seven genes have been associated with PFBC, including four dominant inherited genes (SLC20A2, PDGFRB, PDGFB, and XPR1) and three recessive inherited genes (MYORG, JAM2, and CMPK2). Nevertheless, around 50% of patients with PFBC do not have pathogenic variants in these genes, and further PFBC-associated genes are waiting to be identified. The function of currently known genes suggests that PFBC could be caused by the dysfunction of the neurovascular unit, the dysregulation of phosphate homeostasis, or mitochondrial dysfunction. An improved understanding of the underlying pathogenic mechanisms for PFBC may facilitate the development of novel therapies.
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Affiliation(s)
- Shih-Ying Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
| | - Chen-Jui Ho
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
| | - Yan-Ting Lu
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
| | - Chih-Hsiang Lin
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
| | - Min-Yu Lan
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
- Center for Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
| | - Meng-Han Tsai
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
- Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
- Genomics and Proteomics Core Laboratory, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
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Monfrini E, Arienti F, Rinchetti P, Lotti F, Riboldi GM. Brain Calcifications: Genetic, Molecular, and Clinical Aspects. Int J Mol Sci 2023; 24:ijms24108995. [PMID: 37240341 DOI: 10.3390/ijms24108995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/21/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Many conditions can present with accumulation of calcium in the brain and manifest with a variety of neurological symptoms. Brain calcifications can be primary (idiopathic or genetic) or secondary to various pathological conditions (e.g., calcium-phosphate metabolism derangement, autoimmune disorders and infections, among others). A set of causative genes associated with primary familial brain calcification (PFBC) has now been identified, and include genes such as SLC20A2, PDGFB, PDGFRB, XPR1, MYORG, and JAM2. However, many more genes are known to be linked with complex syndromes characterized by brain calcifications and additional neurologic and systemic manifestations. Of note, many of these genes encode for proteins involved in cerebrovascular and blood-brain barrier functions, which both represent key anatomical structures related to these pathological phenomena. As a growing number of genes associated with brain calcifications is identified, pathways involved in these conditions are beginning to be understood. Our comprehensive review of the genetic, molecular, and clinical aspects of brain calcifications offers a framework for clinicians and researchers in the field.
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Affiliation(s)
- Edoardo Monfrini
- Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, 20122 Milan, Italy
| | - Federica Arienti
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, 20122 Milan, Italy
| | - Paola Rinchetti
- Columbia University Irving Medical Center, Center for Motor Neuron Biology and Diseases, Departments of Pathology & Cell Biology and Neurology, New York, NY 10032, USA
| | - Francesco Lotti
- Columbia University Irving Medical Center, Center for Motor Neuron Biology and Diseases, Departments of Pathology & Cell Biology and Neurology, New York, NY 10032, USA
| | - Giulietta M Riboldi
- The Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, Department of Neurology, NYU Langone Health, New York, NY 10017, USA
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7
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The Pathology of Primary Familial Brain Calcification: Implications for Treatment. Neurosci Bull 2022; 39:659-674. [PMID: 36469195 PMCID: PMC10073384 DOI: 10.1007/s12264-022-00980-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 07/10/2022] [Indexed: 12/08/2022] Open
Abstract
AbstractPrimary familial brain calcification (PFBC) is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain, accompanied by various symptoms, such as dystonia, ataxia, parkinsonism, dementia, depression, headaches, and epilepsy. Currently, the etiology of PFBC is largely unknown, and no specific prevention or treatment is available. During the past 10 years, six causative genes (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified in PFBC. In this review, considering mechanistic studies of these genes at the cellular level and in animals, we summarize the pathogenesis and potential preventive and therapeutic strategies for PFBC patients. Our systematic analysis suggests a classification for PFBC genetic etiology based on several characteristics, provides a summary of the known composition of brain calcification, and identifies some potential therapeutic targets for PFBC.
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8
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Classification of Dystonia. Life (Basel) 2022; 12:life12020206. [PMID: 35207493 PMCID: PMC8875209 DOI: 10.3390/life12020206] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/15/2022] [Accepted: 01/24/2022] [Indexed: 12/23/2022] Open
Abstract
Dystonia is a hyperkinetic movement disorder characterized by abnormal movement or posture caused by excessive muscle contraction. Because of its wide clinical spectrum, dystonia is often underdiagnosed or misdiagnosed. In clinical practice, dystonia could often present in association with other movement disorders. An accurate physical examination is essential to describe the correct phenomenology. To help clinicians reaching the proper diagnosis, several classifications of dystonia have been proposed. The current classification consists of axis I, clinical characteristics, and axis II, etiology. Through the application of this classification system, movement disorder specialists could attempt to correctly characterize dystonia and guide patients to the most effective treatment. The aim of this article is to describe the phenomenological spectrum of dystonia, the last approved dystonia classification, and new emerging knowledge.
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9
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Duan RN, Zhao DD, Liu YM, Yan CZ. A heterozygous deletion of PDGFB gene causes paroxysmal kinesigenic dyskinesia with primary familial brain calcification. Parkinsonism Relat Disord 2021; 92:83-87. [PMID: 34736156 DOI: 10.1016/j.parkreldis.2021.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 10/05/2021] [Accepted: 10/16/2021] [Indexed: 11/15/2022]
Abstract
BACKGROUND Primary familial brain calcification (PFBC) is a neurodegenerative disease characterized with calcium deposition in multiple brain regions. Mutations in PDGFB have been discovered in sporadic and familial PFBC cases. While several known variants displayed loss-of function, no complete deletion of platelet-derived growth factor B (PDGFB) has been reported. METHODS For the diagnostic purpose, brain computerized tomography or magnetic resonance imaging scanning and whole-genome sequencing were performed on the proband and family members in the pedigree. RESULTS We identified a heterozygous PDGFB complete deletion in a Chinese pedigree. The proband presented with paroxysmal kinesigenic dyskinesia (PKD), a rare symptom in PFBC. The proband's mother carrying the same mutation was asymptomatic. CONCLUSIONS For the first time, we reported a PFBC with a heterozygous deletion of PDGFB, and provided evidence of haploinsufficiency in the pathogenesis of PFBC.
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Affiliation(s)
- Ruo-Nan Duan
- Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Dan-Dan Zhao
- Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yi-Ming Liu
- Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Chuan-Zhu Yan
- Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Brain Science Research Institute, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China; Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, Shandong, 266035, China.
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10
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Lenglez S, Sablon A, Fénelon G, Boland A, Deleuze JF, Boutoleau-Bretonnière C, Nicolas G, Demoulin JB. Distinct functional classes of PDGFRB pathogenic variants in primary familial brain calcification. Hum Mol Genet 2021; 31:399-409. [PMID: 34494111 DOI: 10.1093/hmg/ddab258] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 01/30/2023] Open
Abstract
Platelet-derived growth factor receptor beta (PDGFRB) is one of the genes associated with primary familial brain calcification (PFBC), an inherited neurological disease (OMIM:173410). Genetic analysis of patients and families revealed at least 13 PDGFRB heterozygous missense variants, including two novel ones described in the present report. Limited experimental data published on five of these variants had suggested that they decrease the receptor activity. No functional information was available on the impact of variants located within the receptor extracellular domains. Here, we performed a comprehensive molecular analysis of PDGFRB variants linked to PFBC. Mutated receptors were transfected in various cell lines to monitor receptor expression, signaling, mitogenic activity, and ligand binding. Four mutants caused a complete loss of tyrosine kinase activity in multiple assays. One of the novel variants, p.Pro154Ser, decreased the receptor expression and abolished binding of platelet-derived growth factor (PDGF-BB). Others showed a partial loss of function related to reduced expression or signaling. Combining clinical, genetic and molecular data, we consider nine variants as pathogenic or likely pathogenic, three as benign or likely benign and one as a variant of unknown significance. We discuss the possible relationship between the variant residual activity, incomplete penetrance, brain calcification and neurological symptoms. In conclusion, we identified distinct molecular mechanisms whereby PDGFRB variants may result in a receptor loss of function. This work will facilitate genetic counselling in PFBC.
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Affiliation(s)
- Sandrine Lenglez
- De Duve Institute, Université catholique de Louvain, BE-1200, Brussels, Belgium
| | - Ariane Sablon
- De Duve Institute, Université catholique de Louvain, BE-1200, Brussels, Belgium
| | - Gilles Fénelon
- Department of Neurology, APHP, CHU Henri Mondor, Créteil, France
| | - Anne Boland
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, F-91057, Evry, France
| | - Jean-François Deleuze
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, F-91057, Evry, France
| | - Claire Boutoleau-Bretonnière
- CHU Nantes, Centre Mémoire Ressource et Recherche (CMRR), Department of Neurology, F-44093, Nantes, France.,Inserm CIC 04, F-4409, Nantes, France
| | - Gaël Nicolas
- Normandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and CNR-MAJ, FHU G4 Génomique, F-76000, Rouen, France
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11
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Ando K, Shih YH, Ebarasi L, Grosse A, Portman D, Chiba A, Mattonet K, Gerri C, Stainier DYR, Mochizuki N, Fukuhara S, Betsholtz C, Lawson ND. Conserved and context-dependent roles for pdgfrb signaling during zebrafish vascular mural cell development. Dev Biol 2021; 479:11-22. [PMID: 34310924 DOI: 10.1016/j.ydbio.2021.06.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 06/17/2021] [Indexed: 12/27/2022]
Abstract
Platelet derived growth factor beta and its receptor, Pdgfrb, play essential roles in the development of vascular mural cells, including pericytes and vascular smooth muscle cells. To determine if this role was conserved in zebrafish, we analyzed pdgfb and pdgfrb mutant lines. Similar to mouse, pdgfb and pdgfrb mutant zebrafish lack brain pericytes and exhibit anatomically selective loss of vascular smooth muscle coverage. Despite these defects, pdgfrb mutant zebrafish did not otherwise exhibit circulatory defects at larval stages. However, beginning at juvenile stages, we observed severe cranial hemorrhage and vessel dilation associated with loss of pericytes and vascular smooth muscle cells in pdgfrb mutants. Similar to mouse, pdgfrb mutant zebrafish also displayed structural defects in the glomerulus, but normal development of hepatic stellate cells. We also noted defective mural cell investment on coronary vessels with concomitant defects in their development. Together, our studies support a conserved requirement for Pdgfrb signaling in mural cells. In addition, these zebrafish mutants provide an important model for definitive investigation of mural cells during early embryonic stages without confounding secondary effects from circulatory defects.
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Affiliation(s)
- Koji Ando
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds Väg 20, SE-751 85, Uppsala, Sweden; Department of Molecular Pathophysiology, Institute of Advanced Medical Sciences, Nippon Medical School, Sendagi Bunkyo-ku, Tokyo, 113 8602, Japan.
| | - Yu-Huan Shih
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01650, United States
| | - Lwaki Ebarasi
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden
| | - Ann Grosse
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01650, United States
| | - Daneal Portman
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01650, United States
| | - Ayano Chiba
- Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, 564 8565, Japan
| | - Kenny Mattonet
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany
| | - Claudia Gerri
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany; Human Embryo and Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Didier Y R Stainier
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany
| | - Naoki Mochizuki
- Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, 564 8565, Japan
| | - Shigetomo Fukuhara
- Department of Molecular Pathophysiology, Institute of Advanced Medical Sciences, Nippon Medical School, Sendagi Bunkyo-ku, Tokyo, 113 8602, Japan
| | - Christer Betsholtz
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds Väg 20, SE-751 85, Uppsala, Sweden; Department of Medicine Huddinge (MedH), Karolinska Institutet, Campus Flemingsberg, Neo, Blickagången 16, Hiss S, Plan 7, SE-141 57, Huddinge, Sweden
| | - Nathan D Lawson
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01650, United States.
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12
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Guérit E, Arts F, Dachy G, Boulouadnine B, Demoulin JB. PDGF receptor mutations in human diseases. Cell Mol Life Sci 2021; 78:3867-3881. [PMID: 33449152 PMCID: PMC11072557 DOI: 10.1007/s00018-020-03753-y] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/16/2020] [Accepted: 12/29/2020] [Indexed: 12/16/2022]
Abstract
PDGFRA and PDGFRB are classical proto-oncogenes that encode receptor tyrosine kinases responding to platelet-derived growth factor (PDGF). PDGFRA mutations are found in gastrointestinal stromal tumors (GISTs), inflammatory fibroid polyps and gliomas, and PDGFRB mutations drive myofibroma development. In addition, chromosomal rearrangement of either gene causes myeloid neoplasms associated with hypereosinophilia. Recently, mutations in PDGFRB were linked to several noncancerous diseases. Germline heterozygous variants that reduce receptor activity have been identified in primary familial brain calcification, whereas gain-of-function mutants are present in patients with fusiform aneurysms, Kosaki overgrowth syndrome or Penttinen premature aging syndrome. Functional analysis of these variants has led to the preclinical validation of tyrosine kinase inhibitors targeting PDGF receptors, such as imatinib, as a treatment for some of these conditions. This review summarizes the rapidly expanding knowledge in this field.
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Affiliation(s)
- Emilie Guérit
- De Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, Box B1.74.05, 1200, Brussels, Belgium
| | - Florence Arts
- De Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, Box B1.74.05, 1200, Brussels, Belgium
| | - Guillaume Dachy
- De Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, Box B1.74.05, 1200, Brussels, Belgium
| | - Boutaina Boulouadnine
- De Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, Box B1.74.05, 1200, Brussels, Belgium
| | - Jean-Baptiste Demoulin
- De Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, Box B1.74.05, 1200, Brussels, Belgium.
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13
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Moura DAP, de Oliveira JRM. The Master of Puppets: Pleiotropy of PDGFRB and its Relationship to Multiple Diseases. J Mol Neurosci 2020; 70:2102-2106. [DOI: 10.1007/s12031-020-01618-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 06/08/2020] [Indexed: 10/23/2022]
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14
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Rutsch F, Buers I, Nitschke Y. Hereditary Disorders of Cardiovascular Calcification. Arterioscler Thromb Vasc Biol 2020; 41:35-47. [PMID: 33176451 DOI: 10.1161/atvbaha.120.315577] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Arterial calcification is a common phenomenon in the elderly, in patients with atherosclerosis or renal failure and in diabetes. However, when present in very young individuals, it is likely to be associated with an underlying hereditary disorder of arterial calcification. Here, we present an overview of the few monogenic disorders presenting with early-onset cardiovascular calcification. These disorders can be classified according to the function of the respective disease gene into (1) disorders caused by an altered purine and phosphate/pyrophosphate metabolism, (2) interferonopathies, and (3) Gaucher disease. The finding of arterial calcification in early life should alert the clinician and prompt further genetic work-up to define the underlying genetic defect, to establish the correct diagnosis, and to enable appropriate therapy.
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Affiliation(s)
- Frank Rutsch
- Department of General Pediatrics, Muenster University Children's Hospital, Germany
| | - Insa Buers
- Department of General Pediatrics, Muenster University Children's Hospital, Germany
| | - Yvonne Nitschke
- Department of General Pediatrics, Muenster University Children's Hospital, Germany
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15
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Hashimoto Y, Campbell M. Tight junction modulation at the blood-brain barrier: Current and future perspectives. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183298. [PMID: 32353377 DOI: 10.1016/j.bbamem.2020.183298] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 03/09/2020] [Accepted: 03/28/2020] [Indexed: 12/14/2022]
Abstract
The blood-brain barrier (BBB) is the one of the most robust physical barriers in the body, comprised of tight junction (TJ) proteins in brain microvascular endothelial cells. The need for drugs to treat central nervous systems diseases is ever increasing, however the presence of the BBB significantly hampers the uptake of drugs into the brain. To overcome or circumvent the barrier, many kinds of techniques are being developed. Modulating the paracellular route by disruption of the TJ complex has been proposed as a potential drug delivery system to treat brain diseases, however, it has several limitations and is still in a developmental stage. However, recent significant advance in medical equipment /tools such as targeted ultra-sound technologies may resolve these limitations. In this review, we introduce recent advances in site- or molecular size-selective BBB disruption/modulation technologies and we include details on pharmacological inhibitory molecules against intercellular TJ proteins to modulate the BBB.
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Affiliation(s)
- Yosuke Hashimoto
- Trinity College Dublin, Smurfit Institute of Genetics, Dublin 2, Ireland.
| | - Matthew Campbell
- Trinity College Dublin, Smurfit Institute of Genetics, Dublin 2, Ireland.
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16
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Abstract
PURPOSE OF REVIEW In the last 7 years, changes in five genes [SLC20A2, PDGFRB, PDGFB, XPR1, and MYORG] have been implicated in the pathogenesis of primary familial brain calcification (PFBC), allowing for genetic delineation of this phenotypically complex neurodegenerative disorder. This review explores how the ensuing plethora of reported PFBC patients and their disease-causing variants improved our understanding of disease, pathogenesis, clinical manifestation, and penetrance. RECENT FINDINGS In PFBC patients, pathogenic changes have been most frequently described in SLC20A2, accounting for approximately the same number of patients as the variants in the other four PFBC genes combined. There is no appreciable relationship between any combination of the following three variables: the type of disease-causing change, the pattern or extent of calcifications, and the presence or nature of clinical manifestation in PFBC patients. Nevertheless, elucidation of underlying genetic factors provided important recent insights into the pathogenic mechanisms of PFBC, which collectively point toward a compromised neurovascular unit. SUMMARY The ongoing clinical and molecular research increases our understanding of PFBC facilitating diagnosis and identifying potential therapeutic targets for this multifaceted and likely underdiagnosed condition.
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17
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Zarb Y, Weber-Stadlbauer U, Kirschenbaum D, Kindler DR, Richetto J, Keller D, Rademakers R, Dickson DW, Pasch A, Byzova T, Nahar K, Voigt FF, Helmchen F, Boss A, Aguzzi A, Klohs J, Keller A. Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response. Brain 2019; 142:885-902. [PMID: 30805583 PMCID: PMC6439320 DOI: 10.1093/brain/awz032] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 12/07/2018] [Accepted: 12/26/2018] [Indexed: 12/17/2022] Open
Abstract
Brain calcifications are commonly detected in aged individuals and accompany numerous brain diseases, but their functional importance is not understood. In cases of primary familial brain calcification, an autosomally inherited neuropsychiatric disorder, the presence of bilateral brain calcifications in the absence of secondary causes of brain calcification is a diagnostic criterion. To date, mutations in five genes including solute carrier 20 member 2 (SLC20A2), xenotropic and polytropic retrovirus receptor 1 (XPR1), myogenesis regulating glycosidase (MYORG), platelet-derived growth factor B (PDGFB) and platelet-derived growth factor receptor β (PDGFRB), are considered causal. Previously, we have reported that mutations in PDGFB in humans are associated with primary familial brain calcification, and mice hypomorphic for PDGFB (Pdgfbret/ret) present with brain vessel calcifications in the deep regions of the brain that increase with age, mimicking the pathology observed in human mutation carriers. In this study, we characterize the cellular environment surrounding calcifications in Pdgfbret/ret animals and show that cells around vessel-associated calcifications express markers for osteoblasts, osteoclasts and osteocytes, and that bone matrix proteins are present in vessel-associated calcifications. Additionally, we also demonstrate the osteogenic environment around brain calcifications in genetically confirmed primary familial brain calcification cases. We show that calcifications cause oxidative stress in astrocytes and evoke expression of neurotoxic astrocyte markers. Similar to previously reported human primary familial brain calcification cases, we describe high interindividual variation in calcification load in Pdgfbret/ret animals, as assessed by ex vivo and in vivo quantification of calcifications. We also report that serum of Pdgfbret/ret animals does not differ in calcification propensity from control animals and that vessel calcification occurs only in the brains of Pdgfbret/ret animals. Notably, ossification of vessels and astrocytic neurotoxic response is associated with specific behavioural and cognitive alterations, some of which are associated with primary familial brain calcification in a subset of patients.
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Affiliation(s)
- Yvette Zarb
- Department of Neurosurgery, Clinical Neuroscience Center, Zurich University Hospital, Zurich University, Zurich, Switzerland.,Neuroscience Center Zurich (ZNZ), University of Zurich and ETH Zurich, Zurich, Switzerland
| | - Ulrike Weber-Stadlbauer
- Institute of Veterinary Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich University, Zurich, Switzerland
| | - Daniel Kirschenbaum
- Department of Neurosurgery, Clinical Neuroscience Center, Zurich University Hospital, Zurich University, Zurich, Switzerland
| | - Diana Rita Kindler
- Institute of Neuropathology, Zurich University Hospital, Zurich University, Zurich, Switzerland
| | - Juliet Richetto
- Institute of Veterinary Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich University, Zurich, Switzerland
| | - Daniel Keller
- Department of Biomedical Engineering, ETH and University of Zurich, Zurich, Switzerland
| | - Rosa Rademakers
- Institute of Diagnostic and Interventional Radiology, Zurich University Hospital, Zurich University, Zurich, Switzerland
| | - Dennis W Dickson
- Institute of Diagnostic and Interventional Radiology, Zurich University Hospital, Zurich University, Zurich, Switzerland
| | - Andreas Pasch
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
| | | | - Khayrun Nahar
- Department of Neurosurgery, Clinical Neuroscience Center, Zurich University Hospital, Zurich University, Zurich, Switzerland
| | - Fabian F Voigt
- Neuroscience Center Zurich (ZNZ), University of Zurich and ETH Zurich, Zurich, Switzerland.,Brain Research Institute, Zurich University, Zurich, Switzerland
| | - Fritjof Helmchen
- Neuroscience Center Zurich (ZNZ), University of Zurich and ETH Zurich, Zurich, Switzerland.,Brain Research Institute, Zurich University, Zurich, Switzerland
| | - Andreas Boss
- Department of Biomedical Engineering, ETH and University of Zurich, Zurich, Switzerland
| | - Adriano Aguzzi
- Department of Neurosurgery, Clinical Neuroscience Center, Zurich University Hospital, Zurich University, Zurich, Switzerland
| | - Jan Klohs
- Institute of Neuropathology, Zurich University Hospital, Zurich University, Zurich, Switzerland
| | - Annika Keller
- Department of Neurosurgery, Clinical Neuroscience Center, Zurich University Hospital, Zurich University, Zurich, Switzerland.,Neuroscience Center Zurich (ZNZ), University of Zurich and ETH Zurich, Zurich, Switzerland
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18
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Huang YT, Zhang LH, Li MF, Cheng L, Zou GY, Zhou HH. A splice site mutation causing exon 6 skipping in SLC20A2 gene in a primary familial brain calcification family. Brain Res Bull 2019; 150:261-265. [PMID: 30634018 DOI: 10.1016/j.brainresbull.2019.01.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 12/24/2018] [Accepted: 01/03/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Primary familial brain calcification (PFBC) is a rare degenerative disease characterized by symmetrical bilateral calcinosis in the basal ganglia and other brain regions. It has an autosomal dominant inheritance pattern in most cases and exhibits genetic heterogeneity. Previous studies reported that SLC20A2, PDGFRB, PDGFB, XPR1 and MYORG are associated with PFBC, with SLC20A2 the main culprit. However, other mutations may also cause PFBC. Here, we performed a study to reveal the contributing mutations that gave rise to PFBC in a Chinese PFBC family. METHODS We recruited a PFBC family consisting of eight patients and eight healthy family members across three generations. Whole-exome sequencing, Sanger sequencing and RT-PCR were used to detect the genetic mutations. RESULTS Whole-exome sequencing revealed that c.730 + 1G > A of SLC20A2 was the candidate pathogenic mutation for the proband in this family. Genomic DNA PCR amplification and Sanger sequencing confirmed that all the patients from the family carried this mutation, while the healthy subjects in the family did not. Complementary DNA (cDNA) PCR amplification and Sanger sequencing confirmed that the patients had a mutation that caused exon 6 skipping in SLC20A2. CONCLUSION We identified a SLC20A2 splicing variant (c.730 + 1G > A) in a PFBC family. This mutation led to an alternative splicing event that skipped exon 6 in SLC20A2.
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Affiliation(s)
- Yuan-Tao Huang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, Hunan, PR China; Department of Neurology, the Brain Hospital of Hunan Province, Changsha 410008, Hunan, PR China
| | - Li-Hua Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, Hunan, PR China
| | - Mei-Fang Li
- Department of Otorhinolaryngology, the Brain Hospital of Hunan Province, Changsha 410008, Hunan, PR China
| | - Lin Cheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, PR China
| | - Guo-Ying Zou
- Department of Clinical Laboratory, the Brain Hospital of Hunan Province, Changsha 410008, Hunan, PR China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, Hunan, PR China.
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19
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Guimier A, Gordon CT, Hully M, Blauwblomme T, Minard-Colin V, Bole-Feysot C, Nitschké P, Oufadem M, Boddaert N, Sarnacki S, Amiel J. A novel de novo PDGFRB variant in a child with severe cerebral malformations, intracerebral calcifications, and infantile myofibromatosis. Am J Med Genet A 2019; 179:1304-1309. [PMID: 31004414 DOI: 10.1002/ajmg.a.61151] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 03/20/2019] [Accepted: 03/22/2019] [Indexed: 12/17/2022]
Abstract
The spectrum of clinical consequences of variants in the Platelet derived growth factor receptor beta (PDGFRB) gene is wide. Missense variants leading to variable loss of signal transduction in vitro have been reported in the idiopathic basal ganglia calcification (IBGC) syndrome Type 4. In contrast, gain-of-function variants have been reported in infantile myofibromatosis, Penttinen syndrome, and Kosaki overgrowth syndrome. Here, we report a patient harboring a novel postzygotic variant in PDGFRB (c.1682_1684del, p.[Arg561_Tyr562delinsHis]) and presenting severe cerebral malformations, intracerebral calcifications, and infantile myofibromatosis. This observation expands the phenotype associated with PDGFRB variants and illustrates the wide clinical spectrum linked to dysregulation of PDGFRB.
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Affiliation(s)
- Anne Guimier
- Laboratory of embryology and genetics of malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.,Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.,Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Christopher T Gordon
- Laboratory of embryology and genetics of malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.,Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France
| | - Marie Hully
- Service de Neuropédiatrie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Thomas Blauwblomme
- Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.,Service de Neurochirurgie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | | | - Christine Bole-Feysot
- Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.,Genomics Platform, INSERM UMR 1163, Institut Imagine, Paris, France
| | - Patrick Nitschké
- Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.,Bioinformatics Platform, INSERM UMR 1163, Institut Imagine, Paris, France
| | - Myriam Oufadem
- Laboratory of embryology and genetics of malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.,Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France
| | - Nathalie Boddaert
- Service de Radiologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, INSERM U1000 and INSERM UMR 1163, Institut Imagine, Paris, France
| | - Sabine Sarnacki
- Sevice de Chirurgie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Jeanne Amiel
- Laboratory of embryology and genetics of malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.,Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.,Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
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20
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Mathorne SW, Sørensen K, Fagerberg C, Bode M, Hertz JM. A novel PDGFRB sequence variant in a family with a mild form of primary familial brain calcification: a case report and a review of the literature. BMC Neurol 2019; 19:60. [PMID: 30979360 PMCID: PMC6460731 DOI: 10.1186/s12883-019-1292-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 03/31/2019] [Indexed: 12/14/2022] Open
Abstract
Background Primary familial brain calcification is a rare autosomal dominant or recessive neurodegenerative disease, characterized by bilateral brain calcifications in different areas of the brain. It is a clinically heterogeneous disease and patients are reported to exhibit a wide spectrum of neurological and psychiatric symptoms. Mutations in five genes have been identified so far including SLC20A2, PDGFRB, PDGFB, XPR1, and MYORG. PDGFRB encodes the platelet-derived growth factor receptor-beta, and is expressed in neurons, vascular smooth muscle cells and pericytes. Patients with a PDGFRB mutation seem to exhibit a milder phenotype and milder brain calcification on brain imaging than patients with SLC20A2 and PDGFB mutations. However, this is based on a few observations so far. Case presentation We present a Danish family with bilateral brain calcifications and mild clinical symptoms of primary familial brain calcification, segregating with a novel PDGFRB sequence variant: c.1834G > A; p.(Gly612Arg), detected by whole exome sequencing. The variant results in physiochemical changes at the amino acid level, and affects a highly conserved nucleotide as well as amino acid. It is located in the tyrosine kinase domain of PDGFRβ. Segregation analysis and in silico analyses predicted the missense variant to be disease causing. Conclusion Our study confirms that PDGFRB mutation carriers in general have a mild clinical phenotype, and basal ganglia calcifications can be detected by a CT scan, also in asymptomatic mutation carriers.
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Affiliation(s)
- Stine Westergaard Mathorne
- Department of Clinical Genetics, Odense University Hospital, J. B. Winsløvs Vej 4, DK-5000, Odense, Denmark
| | - Kristina Sørensen
- Department of Clinical Genetics, Odense University Hospital, J. B. Winsløvs Vej 4, DK-5000, Odense, Denmark
| | - Christina Fagerberg
- Department of Clinical Genetics, Odense University Hospital, J. B. Winsløvs Vej 4, DK-5000, Odense, Denmark
| | - Matthias Bode
- Department of Neurology, Odense University Hospital, Odense, Denmark
| | - Jens Michael Hertz
- Department of Clinical Genetics, Odense University Hospital, J. B. Winsløvs Vej 4, DK-5000, Odense, Denmark. .,Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
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21
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Pericytes in Primary Familial Brain Calcification. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1147:247-264. [PMID: 31147881 DOI: 10.1007/978-3-030-16908-4_11] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pericytes are perivascular cells along capillaries that are critical for the development of a functional vascular bed in the central nervous system and other organs. Pericyte functions in the adult brain are less well understood. Pericytes have been suggested to mediate functional hyperemia at the capillary level, regulate the blood-brain barrier and to give rise to scar tissue after spinal cord injury. Furthermore, pericyte loss has been suggested to precede cognitive decline in mouse models of Alzheimer's disease. Despite this observation, there is no convincing causality between pericyte loss and the pathogenesis of Alzheimer's disease. However, recent loss-of-function mutations in PDGFB and PDGFRB genes have implicated pericytes as the principle cell type affected in primary familiar brain calcification (PFBC), a neuropsychiatric disorder with dominant inheritance. Here we review the role of the PDGFB/PDGFRB signaling pathway in pericyte development and briefly discuss homeostatic functions of pericytes in the brain. We provide an overview of recent studies with mouse models of PFBC and discuss suggested pathogenic mechanisms for PFBC with special reference to pericytes.
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22
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Huang YT, Zhang LH, Li MF, Cheng L, Qu J, Cheng Y, Li X, Zou GY, Zhou HH. Clinical Features of Primary Familial Brain Calcification in 17 Families. Chin Med J (Engl) 2018; 131:2997-3000. [PMID: 30539916 PMCID: PMC6302657 DOI: 10.4103/0366-6999.247218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Indexed: 12/17/2022] Open
Affiliation(s)
- Yuan-Tao Huang
- Department of Clinical Pharmacology, Xiangya Hospital Central South University, Changsha, Hunan 410008, China
| | - Li-Hua Zhang
- Department of Clinical Pharmacology, Xiangya Hospital Central South University, Changsha, Hunan 410008, China
| | - Mei-Fang Li
- Department of Otorhinolaryngology, The Brain Hospital of Hunan Province, Changsha, Hunan 410007, China
| | - Lin Cheng
- Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China
| | - Jian Qu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Yu Cheng
- Department of Clinical Pharmacology, Xiangya Hospital Central South University, Changsha, Hunan 410008, China
| | - Xi Li
- Department of Clinical Pharmacology, Xiangya Hospital Central South University, Changsha, Hunan 410008, China
| | - Guo-Ying Zou
- Department of Clinical Laboratory, The Brain Hospital of Hunan Province, Changsha, Hunan 410007, China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital Central South University, Changsha, Hunan 410008, China
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23
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Ramos EM, Carecchio M, Lemos R, Ferreira J, Legati A, Sears RL, Hsu SC, Panteghini C, Magistrelli L, Salsano E, Esposito S, Taroni F, Richard AC, Tranchant C, Anheim M, Ayrignac X, Goizet C, Vidailhet M, Maltete D, Wallon D, Frebourg T, Pimentel L, Geschwind DH, Vanakker O, Galasko D, Fogel BL, Innes AM, Ross A, Dobyns WB, Alcantara D, O'Driscoll M, Hannequin D, Campion D, Oliveira JR, Garavaglia B, Coppola G, Nicolas G. Primary brain calcification: an international study reporting novel variants and associated phenotypes. Eur J Hum Genet 2018; 26:1462-1477. [PMID: 29955172 PMCID: PMC6138755 DOI: 10.1038/s41431-018-0185-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 03/21/2018] [Accepted: 05/08/2018] [Indexed: 12/17/2022] Open
Abstract
Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.
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Affiliation(s)
- Eliana Marisa Ramos
- Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Miryam Carecchio
- Molecular Neurogenetics Unit, Movement Disorders Section, IRCCS Foundation Carlo Besta Neurological Institute, Via L. Temolo n. 4, Milan, 20116, Italy
- Department of Pediatric Neurology, IRCCS Foundation Carlo Besta Neurological Institute, Via Celoria 11, Milan, 20131, Italy
- PhD Programme in Translational and Molecular Medicine, Milan Bicocca University, Monza, Italy
| | - Roberta Lemos
- Keizo Asami Laboratory, Universidade Federal de Pernambuco, Recife, Brazil
| | - Joana Ferreira
- Keizo Asami Laboratory, Universidade Federal de Pernambuco, Recife, Brazil
| | - Andrea Legati
- Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Renee Louise Sears
- Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Sandy Chan Hsu
- Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Celeste Panteghini
- Molecular Neurogenetics Unit, Movement Disorders Section, IRCCS Foundation Carlo Besta Neurological Institute, Via L. Temolo n. 4, Milan, 20116, Italy
| | - Luca Magistrelli
- Department of Neurology, University of Eastern Piedmont, C.so Mazzini 18, Novara, 28100, Italy
| | - Ettore Salsano
- Department of Clinical Neurosciences, IRCCS Foundation Carlo Besta Neurological Institute, Via Celoria 11, Milan, 20131, Italy
| | - Silvia Esposito
- Department of Pediatric Neurology, IRCCS Foundation Carlo Besta Neurological Institute, Via Celoria 11, Milan, 20131, Italy
| | - Franco Taroni
- IRCCS Foundation Carlo Besta Neurological Institute, Via Amadeo 42, Milan, 20133, Italy
| | - Anne-Claire Richard
- Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France
| | - Christine Tranchant
- Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Strasbourg, Illkirch, France
| | - Mathieu Anheim
- Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Strasbourg, Illkirch, France
| | - Xavier Ayrignac
- Department of Neurology, Montpellier University Hospital, Montpellier, France
| | - Cyril Goizet
- CHU Bordeaux, Service de Génétique Médicale, 33000, Bordeaux, France
- INSERM U1211, Univ Bordeaux, Laboratoire Maladies Rares, Génétique et Métabolisme, 33000, Bordeaux, France
| | - Marie Vidailhet
- Département de neurologie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, UPMC Univ Paris 06, Inserm U1127, CNRS UMR 7225, ICM, F-75013, Sorbonne Universites, Paris, France
| | - David Maltete
- Normandie Univ, UNIROUEN, Inserm U1073, Rouen University Hospital, Department of Neurology, F 76000, Rouen, France
| | - David Wallon
- Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France
| | - Thierry Frebourg
- Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France
| | - Lylyan Pimentel
- Keizo Asami Laboratory, Universidade Federal de Pernambuco, Recife, Brazil
| | - Daniel H Geschwind
- Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Olivier Vanakker
- Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000, Ghent, Belgium
| | - Douglas Galasko
- Veterans Affairs Medical Center, San Diego and University of California, San Diego, USA
| | - Brent L Fogel
- Departments of Neurology and Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - A Micheil Innes
- Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Alison Ross
- Department of Clinical Genetics, Ashgrove House, Foresterhill, Aberdeen, UK
| | - William B Dobyns
- Departments of Pediatrics and Neurology, University of Washington; and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Diana Alcantara
- Genome Damage & Stability Centre, University of Sussex, Brighton, UK
| | - Mark O'Driscoll
- Genome Damage & Stability Centre, University of Sussex, Brighton, UK
| | - Didier Hannequin
- Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology, Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France
| | - Dominique Campion
- Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France
- Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, Rouen, France
| | - João R Oliveira
- Keizo Asami Laboratory, Universidade Federal de Pernambuco, Recife, Brazil
| | - Barbara Garavaglia
- Molecular Neurogenetics Unit, Movement Disorders Section, IRCCS Foundation Carlo Besta Neurological Institute, Via L. Temolo n. 4, Milan, 20116, Italy
| | - Giovanni Coppola
- Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
| | - Gaël Nicolas
- Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France.
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Nicolas G, Charbonnier C, Campion D, Veltman JA. Estimation of minimal disease prevalence from population genomic data: Application to primary familial brain calcification. Am J Med Genet B Neuropsychiatr Genet 2018; 177:68-74. [PMID: 29152850 DOI: 10.1002/ajmg.b.32605] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 09/22/2017] [Indexed: 12/13/2022]
Abstract
Primary Familial Brain Calcification (PFBC) is a rare calcifying disorder of the brain with autosomal dominant inheritance, of unknown prevalence. Four causal genes have been identified so far: SLC20A2, PDGFB, PDGFRB, and XPR1, with pathogenic, probably pathogenic or missense variants of unknown significance found in 27.7% probands in the French PFBC series. Estimating PFBC prevalence from a clinical input is arduous due to a large diversity of symptoms and ages of onset and to incomplete clinical penetrance. Abnormal calcifications on CT scan can be used as a reliable diagnostic biomarker whatever the clinical status, but differential diagnoses should be ruled out including the challenging exclusion of common basal ganglia calcifications. Our primary aim was to estimate the minimal prevalence of PFBC due to a variant in one of the known genes. We extracted variants from the four known genes present in the gnomAD database gathering genomic data from 138,632 individuals. We interpreted all variants based on their predicted effect, their frequency, and previous studies on PFBC patients. Using the most conservative estimate, the minimal prevalence of PFBC related to a variant in one of the four known genes was 4.5 p. 10,000 (95%CI [3.4-5.5] p. 10,000). We then used variant detection rates in patients to extrapolate an overall minimal prevalence of PFBC to 2.1 p. 1,000 (95%CI [1.9-2.4] p. 1,000). The population-based genomic analysis indicates that PFBC is not an exceptionally rare disorder, still underestimated and underdiagnosed.
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Affiliation(s)
- Gaël Nicolas
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Genetics and CNR-MAJ, F 76000, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, Rouen, France
| | - Camille Charbonnier
- Department of Genetics and CNR-MAJ, F 76000, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, Rouen, France
| | - Dominique Campion
- Department of Genetics and CNR-MAJ, F 76000, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, Rouen, France.,Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France
| | - Joris A Veltman
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.,Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom
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25
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Quintáns B, Oliveira J, Sobrido MJ. Primary familial brain calcifications. HANDBOOK OF CLINICAL NEUROLOGY 2018; 147:307-317. [PMID: 29325620 DOI: 10.1016/b978-0-444-63233-3.00020-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Primary familial brain calcification (PFBC) is a neurodegenerative disease with characteristic calcium deposits in the basal ganglia and other brain regions. The disease usually presents as a combination of abnormal movements, cognitive and psychiatric manifestations, clinically indistinguishable from other adult-onset neurodegenerative disorders. The differential diagnosis must be established with genetic and nongenetic disorders that can also lead to calcium deposits in encephalic structures. In the past years PFBC causal mutations have been discovered in genes related to calcium phosphate homeostasis (SLC20A2, XPR1) and in genes involved with endothelial function and integrity (PDGFB, PDGFRB). The most frequently mutated gene is SLC20A2, where mutations can affect any domain of the protein. There is no clearcut relationship between the specific mutation/gene, onset age, neuroimaging pattern, and severity of clinical manifestations. The discovery of the genetic basis of PFBC provides not only a diagnostic tool, but also an insight into the pathomechanisms and potential therapeutic trials for this rare disease.
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Affiliation(s)
- Beatriz Quintáns
- Instituto de Investigación Sanitaria (IDIS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain
| | | | - María-Jesús Sobrido
- Instituto de Investigación Sanitaria (IDIS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain.
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26
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DeMeo NN, Burgess JD, Blackburn PR, Gass JM, Richter J, Atwal HK, van Gerpen JA, Atwal PS. Co-occurrence of a novel PDGFRB variant and likely pathogenic variant in CASR in an individual with extensive intracranial calcifications and hypocalcaemia. Clin Case Rep 2017; 6:8-13. [PMID: 29375828 PMCID: PMC5771904 DOI: 10.1002/ccr3.1265] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 09/20/2017] [Accepted: 10/08/2017] [Indexed: 12/12/2022] Open
Abstract
This case report describes an individual with brain calcifications, cognitive decline, motor dysfunction, and hypocalcaemia. Exome sequencing revealed a previously reported variant in the CASR gene and a variant of uncertain significance in PDGFRB. The clinical phenotype is likely explained by the CASR variant, but we discuss how the PDGFRB variant could also participate in the phenotype.
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Affiliation(s)
| | | | - Patrick R Blackburn
- Center for Individualized Medicine Mayo Clinic Jacksonville Florida.,Department of Health Sciences Research Mayo Clinic Jacksonville Florida
| | - Jennifer M Gass
- Center for Individualized Medicine Mayo Clinic Jacksonville Florida
| | - John Richter
- Center for Individualized Medicine Mayo Clinic Jacksonville Florida.,Department of Clinical Genomics Mayo Clinic Jacksonville Florida
| | | | | | - Paldeep S Atwal
- Center for Individualized Medicine Mayo Clinic Jacksonville Florida.,Department of Clinical Genomics Mayo Clinic Jacksonville Florida
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27
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Koyama S, Sato H, Kobayashi R, Kawakatsu S, Kurimura M, Wada M, Kawanami T, Kato T. Clinical and radiological diversity in genetically confirmed primary familial brain calcification. Sci Rep 2017; 7:12046. [PMID: 28935882 PMCID: PMC5608910 DOI: 10.1038/s41598-017-11595-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 08/25/2017] [Indexed: 01/03/2023] Open
Abstract
Primary familial brain calcification (PFBC) is a rare neuropsychiatric disorder with characteristic symmetrical brain calcifications. Patients with PFBC may have a variety of symptoms, although they also may be clinically asymptomatic. Parkinsonism is one of the most common movement disorders; however, the underlying mechanism remains unclear. This condition is typically transmitted in an autosomal dominant fashion. To date, mutations in SLC20A2, PDGFRB, PDGFB, and XPR1 have been reported to cause PFBC. The aim of the study was to identify the genetic cause of brain calcification in probands from three PFBC families and in 8 sporadic patients and to perform clinical and radiological assessments focusing on parkinsonism in mutation carriers. Three familial PFBC probands and their relatives and eight sporadic patients affected with brain calcifications were enrolled in this study. Whole-exome sequencing identified three novel mutations: c.269G > T, p.(Gly90Val) and c.516+1G > A in SLC20A2 in familial cases, and c.602-1G > T in PDGFB in a sporadic patient. The c.516+1G > A mutation resulted in exon 4 skipping in SLC20A2 (p.Val144Glyfs*85). Dopamine transporter single photon emission computed tomography using 123I-ioflupane and 123I-metaiodobenzylguanidine cardiac scintigraphy revealed pre-synaptic dopaminergic deficit and cardiac sympathetic nerve dysfunction in two SLC20A2-related PFBC patients with parkinsonism.
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Affiliation(s)
- Shingo Koyama
- Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
| | - Hidenori Sato
- Genomic Information Analysis Unit, Department of Genomic Cohort Research, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan
| | - Ryota Kobayashi
- Department of Psychiatry, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan
| | - Shinobu Kawakatsu
- Department of Neuropsychiatry, Aizu Medical Center, Fukushima Medical University, 21-2 Maeda, Tanisawa, Kawahigashi, Aizuwakamatsu, Fukushima, 969-3492, Japan
| | - Masayuki Kurimura
- Department of Neurology, Okitama Public General Hospital, 2000 Nishi-otsuka, Kawanishi-machi, Higashi-okitama-gun, Yamagata, 992-0601, Japan
| | - Manabu Wada
- Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan
| | - Toru Kawanami
- Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan
| | - Takeo Kato
- Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan
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28
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Jaworski K, Styczyńska M, Mandecka M, Walecki J, Kosior DA. Fahr Syndrome - an Important Piece of a Puzzle in the Differential Diagnosis of Many Diseases. Pol J Radiol 2017; 82:490-493. [PMID: 29662577 PMCID: PMC5894054 DOI: 10.12659/pjr.902024] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 12/06/2016] [Indexed: 01/30/2023] Open
Abstract
Fahr syndrome is a rare neurodegenerative disorder characterized by symmetrical, bilateral calcifications in the basal ganglia, nucleus gyrus and cerebral cortex. The continuous advancement as well as widespread use of brain imaging have contributed to the increasing detection rates of such changes. Nevertheless, their etiology is understood only partially and the methods of causative treatment are limited. Due to various symptoms, Fahr syndrome may resemble diseases from the field of neurology, psychiatry, cardiology and even urology. This article provides an up-to-date review of the literature concerning Fahr syndrome in terms of clinical practice.
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Affiliation(s)
- Krzysztof Jaworski
- Department of Cardiology and Hypertension, Central Clinical Hospital of The Ministry of Interior, Warsaw, Poland
| | - Maria Styczyńska
- Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Monika Mandecka
- Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Jerzy Walecki
- Department of Radiology, Postgraduate Medical School, Warsaw, Poland
| | - Dariusz A. Kosior
- Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
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29
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Abstract
PURPOSE OF REVIEW We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease. RECENT FINDINGS Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.
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MESH Headings
- Abnormalities, Multiple/drug therapy
- Abnormalities, Multiple/genetics
- Abnormalities, Multiple/metabolism
- Aortic Diseases/drug therapy
- Aortic Diseases/genetics
- Aortic Diseases/metabolism
- Basal Ganglia Diseases/drug therapy
- Basal Ganglia Diseases/genetics
- Basal Ganglia Diseases/metabolism
- Calcinosis/drug therapy
- Calcinosis/genetics
- Calcinosis/metabolism
- Cartilage Diseases/drug therapy
- Cartilage Diseases/genetics
- Cartilage Diseases/metabolism
- Dental Enamel Hypoplasia/drug therapy
- Dental Enamel Hypoplasia/genetics
- Dental Enamel Hypoplasia/metabolism
- Diphosphates/metabolism
- Enzyme Replacement Therapy
- Gaucher Disease/drug therapy
- Gaucher Disease/genetics
- Gaucher Disease/metabolism
- Hand Deformities, Congenital/drug therapy
- Hand Deformities, Congenital/genetics
- Hand Deformities, Congenital/metabolism
- Humans
- Hyperostosis, Cortical, Congenital/drug therapy
- Hyperostosis, Cortical, Congenital/genetics
- Hyperostosis, Cortical, Congenital/metabolism
- Hyperphosphatemia/drug therapy
- Hyperphosphatemia/genetics
- Hyperphosphatemia/metabolism
- Interferons/metabolism
- Metacarpus/abnormalities
- Metacarpus/metabolism
- Muscular Diseases/drug therapy
- Muscular Diseases/genetics
- Muscular Diseases/metabolism
- Odontodysplasia/drug therapy
- Odontodysplasia/genetics
- Odontodysplasia/metabolism
- Osteoporosis/drug therapy
- Osteoporosis/genetics
- Osteoporosis/metabolism
- Phosphates/metabolism
- Progeria/drug therapy
- Progeria/genetics
- Progeria/metabolism
- Pseudoxanthoma Elasticum/drug therapy
- Pseudoxanthoma Elasticum/genetics
- Pseudoxanthoma Elasticum/metabolism
- Pulmonary Valve Stenosis/drug therapy
- Pulmonary Valve Stenosis/genetics
- Pulmonary Valve Stenosis/metabolism
- Vascular Calcification/drug therapy
- Vascular Calcification/genetics
- Vascular Calcification/metabolism
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Affiliation(s)
- Yvonne Nitschke
- Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany
| | - Frank Rutsch
- Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany.
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30
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Wang C, Yao XP, Chen HT, Lai JH, Guo XX, Su HZ, Dong EL, Zhang QJ, Wang N, Chen WJ. Novel mutations of PDGFRB cause primary familial brain calcification in Chinese families. J Hum Genet 2017; 62:697-701. [PMID: 28298627 DOI: 10.1038/jhg.2017.25] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 01/18/2017] [Accepted: 01/20/2017] [Indexed: 02/08/2023]
Abstract
Four causative genes, including solute carrier family 20 member 2 (SLC20A2), platelet-derived growth factor receptor b (PDGFRB), platelet-derived growth factor b (PDGFB)and xenotropic and polytropic retrovirus receptor 1 (XPR1), have been identified to cause primary familial brain calcification (PFBC). However, PDGFRB mutations seem to be quite rare and no PDGFRB mutations have been reported in Chinese PFBC patients. A total of 146 PFBC patients including 12 families and 134 sporadic patients were recruited in this study. All of them were previously tested negative for the SLC20A2. Mutational analyses of the entire exons and exon-intron boundaries of PDGFRB were carried out by direct gene sequencing. In silico analyses of the identified variants were conducted using Mutation Taster, PolyPhen-2 and Sorts Intolerant From Tolerant. Two heterozygous variants, c.3G>A and c.2209G>A, of the PDGFRB gene were revealed in two PFBC families, respectively. These two variants were not observed in 200 healthy controls. The variant c.3G>A was located in exon 2 and affected the initiation codon of the PDGFRB gene. The variant c.2209G>A resulted in amino-acid substitutions of aspartic acid to asparagine at position 737. Both of these two variants co-segregated with the disease phenotype (variant carriers in Family 1: I1, II2 and II3; variant carriers in Family 2: I2 and II8), suggesting a pathogenic impact of these variants. The prevalence of PDGFRB mutations in Chinese PFBC patients seems to be quite low, indicating that PDGFRB is not a major causative gene of PFBC in Chinese population.
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Affiliation(s)
- Chong Wang
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Xiang-Ping Yao
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Hai-Ting Chen
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Jing-Hui Lai
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Xin-Xin Guo
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Hui-Zhen Su
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - En-Lin Dong
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Qi-Jie Zhang
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ning Wang
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Wan-Jin Chen
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Molecular Neurology, Fuzhou, China
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31
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Recurrent Somatic PDGFRB Mutations in Sporadic Infantile/Solitary Adult Myofibromas But Not in Angioleiomyomas and Myopericytomas. Am J Surg Pathol 2017; 41:195-203. [DOI: 10.1097/pas.0000000000000752] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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32
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Marras C, Lang A, van de Warrenburg BP, Sue CM, Tabrizi SJ, Bertram L, Mercimek-Mahmutoglu S, Ebrahimi-Fakhari D, Warner TT, Durr A, Assmann B, Lohmann K, Kostic V, Klein C. Nomenclature of genetic movement disorders: Recommendations of the international Parkinson and movement disorder society task force. Mov Disord 2016; 31:436-57. [PMID: 27079681 DOI: 10.1002/mds.26527] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 10/21/2015] [Accepted: 11/22/2015] [Indexed: 12/11/2022] Open
Abstract
The system of assigning locus symbols to specify chromosomal regions that are associated with a familial disorder has a number of problems when used as a reference list of genetically determined disorders,including (I) erroneously assigned loci, (II) duplicated loci, (III) missing symbols or loci, (IV) unconfirmed loci and genes, (V) a combination of causative genes and risk factor genes in the same list, and (VI) discordance between phenotype and list assignment. In this article, we report on the recommendations of the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders and present a system for naming genetically determined movement disorders that addresses these problems. We demonstrate how the system would be applied to currently known genetically determined parkinsonism, dystonia, dominantly inherited ataxia, spastic paraparesis, chorea, paroxysmal movement disorders, neurodegeneration with brain iron accumulation, and primary familial brain calcifications. This system provides a resource for clinicians and researchers that, unlike the previous system, can be considered an accurate and criterion-based list of confirmed genetically determined movement disorders at the time it was last updated.
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Affiliation(s)
- Connie Marras
- Toronto Western Hospital Morton, Gloria Shulman Movement Disorders Centre, and the Edmond J. Safra Program in Parkinson's Disease, University of Toronto, Toronto, Canada
| | - Anthony Lang
- Toronto Western Hospital Morton, Gloria Shulman Movement Disorders Centre, and the Edmond J. Safra Program in Parkinson's Disease, University of Toronto, Toronto, Canada
| | - Bart P van de Warrenburg
- Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Carolyn M Sue
- Department of Neurology, Royal North Shore Hospital and Kolling Institute of Medical Research, University of Sydney, St. Leonards, New South Wales, Australia
| | - Sarah J Tabrizi
- Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK
| | - Lars Bertram
- Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany
- School of Public Health, Faculty of Medicine, Imperial College, London, UK
| | - Saadet Mercimek-Mahmutoglu
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada
| | - Darius Ebrahimi-Fakhari
- Division of Pediatric Neurology and Inborn Errors of Metabolism, Department of Pediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
- Department of Neurology & F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Thomas T Warner
- Reta Lila Weston Institute of Neurological Studies, Department of Molecular Neurosciences, UCL Institute of Neurology, London, UK
| | - Alexandra Durr
- Sorbonne Université, UPMC, Inserm and Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France
| | - Birgit Assmann
- Division of Pediatric Neurology, Department of Pediatrics I, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg
| | - Katja Lohmann
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Vladimir Kostic
- Institute of Neurology, School of Medicine University of Belgrade, Belgrade, Serbia
| | - Christine Klein
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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33
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Kimura T, Miura T, Aoki K, Saito S, Hondo H, Konno T, Uchiyama A, Ikeuchi T, Takahashi H, Kakita A. Familial idiopathic basal ganglia calcification: Histopathologic features of an autopsied patient with an SLC20A2 mutation. Neuropathology 2015; 36:365-71. [PMID: 26635128 DOI: 10.1111/neup.12280] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 11/10/2015] [Accepted: 11/10/2015] [Indexed: 12/17/2022]
Abstract
Idiopathic basal ganglia calcification (IBGC), or Fahr's disease, is a neurological disorder characterized by widespread calcification in the brain. Recently, several causative genes have been identified, but the histopathologic features of the brain lesions and expression of the gene products remain unclear. Here, we report the clinical and autopsy features of a 62-year-old Japanese man with familial IBGC, in whom an SLC20A2 mutation was identified. The patient developed mild cognitive impairment and parkinsonism. A brain CT scan demonstrated abnormal calcification in the bilateral basal ganglia, thalami and cerebellum. An MRI study at this point revealed glioblastoma, and the patient died 6 months later. At autopsy, symmetric calcification in the basal ganglia, thalami, cerebellar white matter and deeper layers of the cerebral cortex was evident. The calcification was observed in the tunica media of small arteries, arterioles and capillaries, but not in veins. Immunohistochemistry using an antibody against type III sodium-dependent phosphate transporter 2 (PiT-2), the SLC20A2 product, demonstrated that astrocytic processes were labeled in several regions in control brains, whereas in the patient, reactivity in astrocytes was apparently weak. Immunoblotting demonstrated a marked decrease of PiT-2 in the patient. There are few autopsy reports of IBGC patients with confirmation of the genetic background. The autopsy features seem informative for better understanding the histogenesis of IBGC lesions.
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Affiliation(s)
- Tadashi Kimura
- Departments of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan
| | - Takeshi Miura
- Departments of Neurology, Brain Research Institute, University of Niigata, Niigata, Japan.,Departments of Neurology, Toyama Prefectural Central Hospital, Toyama, Japan
| | - Kenju Aoki
- Departments of Neurology, Toyama Prefectural Central Hospital, Toyama, Japan
| | - Shoji Saito
- Departments of Neurosurgery, Toyama Prefectural Central Hospital, Toyama, Japan
| | - Hiroaki Hondo
- Departments of Neurosurgery, Toyama Prefectural Central Hospital, Toyama, Japan
| | - Takuya Konno
- Departments of Neurology, Brain Research Institute, University of Niigata, Niigata, Japan
| | - Akio Uchiyama
- Departments of Pathology, Toyama Prefectural Central Hospital, Toyama, Japan
| | - Takeshi Ikeuchi
- Departments of Molecular Genetics, Brain Research Institute, University of Niigata, Niigata, Japan
| | - Hitoshi Takahashi
- Departments of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan
| | - Akiyoshi Kakita
- Departments of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan
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Vanlandewijck M, Lebouvier T, Andaloussi Mäe M, Nahar K, Hornemann S, Kenkel D, Cunha SI, Lennartsson J, Boss A, Heldin CH, Keller A, Betsholtz C. Functional Characterization of Germline Mutations in PDGFB and PDGFRB in Primary Familial Brain Calcification. PLoS One 2015; 10:e0143407. [PMID: 26599395 PMCID: PMC4658112 DOI: 10.1371/journal.pone.0143407] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 09/25/2015] [Indexed: 12/17/2022] Open
Abstract
Primary Familial Brain Calcification (PFBC), a neurodegenerative disease characterized by progressive pericapillary calcifications, has recently been linked to heterozygous mutations in PDGFB and PDGFRB genes. Here, we functionally analyzed several of these mutations in vitro. All six analyzed PDGFB mutations led to complete loss of PDGF-B function either through abolished protein synthesis or through defective binding and/or stimulation of PDGF-Rβ. The three analyzed PDGFRB mutations had more diverse consequences. Whereas PDGF-Rβ autophosphorylation was almost totally abolished in the PDGFRB L658P mutation, the two sporadic PDGFRB mutations R987W and E1071V caused reductions in protein levels and specific changes in the intensity and kinetics of PLCγ activation, respectively. Since at least some of the PDGFB mutations were predicted to act through haploinsufficiency, we explored the consequences of reduced Pdgfb or Pdgfrb transcript and protein levels in mice. Heterozygous Pdgfb or Pdgfrb knockouts, as well as double Pdgfb+/-;Pdgfrb+/- mice did not develop brain calcification, nor did Pdgfrbredeye/redeye mice, which show a 90% reduction of PDGFRβ protein levels. In contrast, Pdgfbret/ret mice, which have altered tissue distribution of PDGF-B protein due to loss of a proteoglycan binding motif, developed brain calcifications. We also determined pericyte coverage in calcification-prone and non-calcification-prone brain regions in Pdgfbret/ret mice. Surprisingly and contrary to our hypothesis, we found that the calcification-prone brain regions in Pdgfbret/ret mice model had a higher pericyte coverage and a more intact blood-brain barrier (BBB) compared to non-calcification-prone brain regions. While our findings provide clear evidence that loss-of-function mutations in PDGFB or PDGFRB cause PFBC, they also demonstrate species differences in the threshold levels of PDGF-B/PDGF-Rβ signaling that protect against small-vessel calcification in the brain. They further implicate region-specific susceptibility factor(s) in PFBC pathogenesis that are distinct from pericyte and BBB deficiency.
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Affiliation(s)
- Michael Vanlandewijck
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, Uppsala 75185, Sweden
- Integrated Cardio Metabolic Centre (ICMC), Karolinska Institute, Novum, SE-141 57 Huddinge, Stockholm, Sweden
| | - Thibaud Lebouvier
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, Uppsala 75185, Sweden
| | - Maarja Andaloussi Mäe
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, Uppsala 75185, Sweden
| | - Khayrun Nahar
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, Uppsala 75185, Sweden
| | - Simone Hornemann
- Institute of Neuropathology, University Hospital Zürich, Zürich University, CH-8091 Zürich, Switzerland
| | - David Kenkel
- Institute of Diagnostic and Interventional Radiology, University Hospital Zürich, Zürich University, CH-8091 Zürich, Switzerland
| | - Sara I. Cunha
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, Uppsala 75185, Sweden
- Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, SE-75124, Uppsala, Sweden
| | - Johan Lennartsson
- Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, SE-75124, Uppsala, Sweden
| | - Andreas Boss
- Institute of Diagnostic and Interventional Radiology, University Hospital Zürich, Zürich University, CH-8091 Zürich, Switzerland
| | - Carl-Henrik Heldin
- Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, SE-75124, Uppsala, Sweden
| | - Annika Keller
- Division of Neurosurgery, University Hospital Zürich, Zürich University, CH-8091 Zürich, Switzerland
| | - Christer Betsholtz
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, Uppsala 75185, Sweden
- * E-mail:
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35
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Johnston J, Sanchez-Contreras M, Keppler-Noreuil K, Sapp J, Crenshaw M, Finch N, Cormier-Daire V, Rademakers R, Sybert V, Biesecker L. A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome. Am J Hum Genet 2015; 97:465-74. [PMID: 26279204 DOI: 10.1016/j.ajhg.2015.07.009] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 07/21/2015] [Indexed: 01/30/2023] Open
Abstract
Penttinen syndrome is a distinctive disorder characterized by a prematurely aged appearance with lipoatrophy, epidermal and dermal atrophy along with hypertrophic lesions that resemble scars, thin hair, proptosis, underdeveloped cheekbones, and marked acro-osteolysis. All individuals have been simplex cases. Exome sequencing of an affected individual identified a de novo c.1994T>C p.Val665Ala variant in PDGFRB, which encodes the platelet-derived growth factor receptor β. Three additional unrelated individuals with this condition were shown to have the identical variant in PDGFRB. Distinct mutations in PDGFRB have been shown to cause infantile myofibromatosis, idiopathic basal ganglia calcification, and an overgrowth disorder with dysmorphic facies and psychosis, none of which overlaps with the clinical findings in Penttinen syndrome. We evaluated the functional consequence of this causative variant on the PDGFRB signaling pathway by transfecting mutant and wild-type cDNA into HeLa cells, and transfection showed ligand-independent constitutive signaling through STAT3 and PLCγ. Penttinen syndrome is a clinically distinct genetic condition caused by a PDGFRB gain-of-function mutation that is associated with a specific and unusual perturbation of receptor function.
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36
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Vilder EYGD, Vanakker OM. From variome to phenome: Pathogenesis, diagnosis and management of ectopic mineralization disorders. World J Clin Cases 2015; 3:556-574. [PMID: 26244149 PMCID: PMC4517332 DOI: 10.12998/wjcc.v3.i7.556] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Revised: 02/27/2015] [Accepted: 05/18/2015] [Indexed: 02/05/2023] Open
Abstract
Ectopic mineralization - inappropriate biomineralization in soft tissues - is a frequent finding in physiological aging processes and several common disorders, which can be associated with significant morbidity and mortality. Further, pathologic mineralization is seen in several rare genetic disorders, which often present life-threatening phenotypes. These disorders are classified based on the mechanisms through which the mineralization occurs: metastatic or dystrophic calcification or ectopic ossification. Underlying mechanisms have been extensively studied, which resulted in several hypotheses regarding the etiology of mineralization in the extracellular matrix of soft tissue. These hypotheses include intracellular and extracellular mechanisms, such as the formation of matrix vesicles, aberrant osteogenic and chondrogenic signaling, apoptosis and oxidative stress. Though coherence between the different findings is not always clear, current insights have led to improvement of the diagnosis and management of ectopic mineralization patients, thus translating pathogenetic knowledge (variome) to the phenotype (phenome). In this review, we will focus on the clinical presentation, pathogenesis and management of primary genetic soft tissue mineralization disorders. As examples of dystrophic calcification disorders Pseudoxanthoma elasticum, Generalized arterial calcification of infancy, Keutel syndrome, Idiopathic basal ganglia calcification and Arterial calcification due to CD73 (NT5E) deficiency will be discussed. Hyperphosphatemic familial tumoral calcinosis will be reviewed as an example of mineralization disorders caused by metastatic calcification.
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37
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Dusek P, Litwin T, Czlonkowska A. Wilson disease and other neurodegenerations with metal accumulations. Neurol Clin 2015; 33:175-204. [PMID: 25432729 DOI: 10.1016/j.ncl.2014.09.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Trace elements, such as iron, copper, manganese, and calcium, which are essential constituents necessary for cellular homeostasis, become toxic when present in excess quantities. In this article, we describe disorders arising from endogenous dysregulation of metal homeostasis leading to their tissue accumulation. Although subgroups of these diseases lead to regional brain metal accumulation, mostly in globus pallidus, which is susceptible to accumulate divalent metal ions, other subgroups cause systemic metal accumulation affecting the whole brain, liver, and other parenchymal organs. The latter group comprises Wilson disease, manganese transporter deficiency, and aceruloplasminemia and responds favorably to chelation treatment.
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Affiliation(s)
- Petr Dusek
- Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital in Prague, Charles University in Prague, Kateřinská 30, Prague 128 21, Czech Republic; Institute of Neuroradiology, University Medicine Goettingen, Robert-Koch-Street 40, Göttingen 37075, Germany.
| | - Tomasz Litwin
- 2nd Department of Neurology, Institute Psychiatry and Neurology, Sobieskiego 9, Warsaw 02-957, Poland
| | - Anna Czlonkowska
- 2nd Department of Neurology, Institute Psychiatry and Neurology, Sobieskiego 9, Warsaw 02-957, Poland; Department of Experimental and Clinical Pharmacology, Medical University, Banacha 1b, Warsaw 02-097, Poland
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38
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Deng H, Zheng W, Jankovic J. Genetics and molecular biology of brain calcification. Ageing Res Rev 2015; 22:20-38. [PMID: 25906927 DOI: 10.1016/j.arr.2015.04.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 04/14/2015] [Accepted: 04/15/2015] [Indexed: 01/01/2023]
Abstract
Brain calcification is a common neuroimaging finding in patients with neurological, metabolic, or developmental disorders, mitochondrial diseases, infectious diseases, traumatic or toxic history, as well as in otherwise normal older people. Patients with brain calcification may exhibit movement disorders, seizures, cognitive impairment, and a variety of other neurologic and psychiatric symptoms. Brain calcification may also present as a single, isolated neuroimaging finding. When no specific cause is evident, a genetic etiology should be considered. The aim of the review is to highlight clinical disorders associated with brain calcification and provide summary of current knowledge of diagnosis, genetics, and pathogenesis of brain calcification.
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Affiliation(s)
- Hao Deng
- Department of Neurology, Third Xiangya Hospital, Central South University, Changsha, China; Center for Experimental Medicine, Third Xiangya Hospital, Central South University, Changsha, China.
| | - Wen Zheng
- Department of Neurology, Third Xiangya Hospital, Central South University, Changsha, China; Center for Experimental Medicine, Third Xiangya Hospital, Central South University, Changsha, China
| | - Joseph Jankovic
- Department of Neurology, Baylor College of Medicine, Houston, TX, USA
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Abstract
Bilateral accumulation of calcium in the brain, most commonly in the basal ganglia, but also in the cerebellum, thalamus, and brainstem can be inherited in an autosomal dominant fashion and is then referred to as primary familial brain calcifications (PFBC). Clinical manifestations include a spectrum of movement disorders and neuropsychiatric abnormalities. In the past 2 years, 3 genes have been identified to cause PFBC, (ie, SLC20A2, PDGFRB, and PDGFB). SCL20A2 encodes the Type III sodium-dependent inorganic phosphate (Pi) transporter 2 (PiT2) and, when mutated, uptake of Pi is severely impaired likely causing buildup of calcium phosphate. The second identified cause of PFBC is mutations in PDGFRB, which codes for platelet-derived growth factor receptor β (PDGF-Rβ). Interestingly, the third PFBC gene is PDGFB that encodes the ligand of PDGF-Rβ, which is secreted during angiogenesis to recruit pericytes, thereby implying impairment of the blood-brain barrier as a disease mechanism of PFBC.
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Affiliation(s)
- Ana Westenberger
- Institute of Neurogenetics, University of Lübeck, Ratzeburger Allee 160, Lübeck, 23538, Germany
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40
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Lemos RR, Ramos EM, Legati A, Nicolas G, Jenkinson EM, Livingston JH, Crow YJ, Campion D, Coppola G, Oliveira JRM. Update and Mutational Analysis of SLC20A2: A Major Cause of Primary Familial Brain Calcification. Hum Mutat 2015; 36:489-95. [PMID: 25726928 DOI: 10.1002/humu.22778] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 02/13/2015] [Indexed: 01/14/2023]
Abstract
Primary familial brain calcification (PFBC) is a heterogeneous neuropsychiatric disorder, with affected individuals presenting a wide variety of motor and cognitive impairments, such as migraine, parkinsonism, psychosis, dementia, and mood swings. Calcifications are usually symmetrical, bilateral, and found predominantly in the basal ganglia, thalamus, and cerebellum. So far, variants in three genes have been linked to PFBC: SLC20A2, PDGFRB, and PDGFB. Variants in SLC20A2 are responsible for most cases identified so far and, therefore, the present review is a comprehensive worldwide summary of all reported variants to date. SLC20A2 encodes an inorganic phosphate transporter, PiT-2, widely expressed in various tissues, including brain, and is part of a major family of solute carrier membrane transporters. Fifty variants reported in 55 unrelated patients so far have been identified in families of diverse ethnicities and only few are recurrent. Various types of variants were detected (missense, nonsense, frameshift) including full or partial SLC20A2 deletions. The recently reported SLC20A2 knockout mouse will enhance our understanding of disease mechanism and allow for screening of therapeutic compounds. In the present review, we also discuss the implications of these recent exciting findings and consider the possibility of treatments based on manipulation of inorganic phosphate homeostasis.
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Affiliation(s)
- Roberta R Lemos
- Keizo Asami Laboratory (LIKA), Universidade Federal de Pernambuco (UFPE), Recife, Brazil
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41
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Taglia I, Bonifati V, Mignarri A, Dotti MT, Federico A. Primary familial brain calcification: update on molecular genetics. Neurol Sci 2015; 36:787-94. [PMID: 25686613 DOI: 10.1007/s10072-015-2110-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 02/10/2015] [Indexed: 12/17/2022]
Abstract
Primary familial brain calcification is a neuropsychiatric disorder with calcium deposits in the brain, especially in basal ganglia, cerebellum and subcortical white matter. The disease is characterized by a clinical heterogeneity, with a various combination of symptoms that include movement disorders and psychiatric disturbances; asymptomatic patients have been also reported. To date, three causative genes have been found: SLC20A2, PDGFRB and PDGFB. SLC20A2 gene codes for the 'sodium-dependent phosphate transporter 2' (PiT-2), a cell membrane transporters of inorganic phosphate, involved in Pi uptake by cells and maintenance of Pi body levels. Over 40 pathogenic variants of SLC20A2 have been reported, affecting the regulation of Pi homeostasis. It was hypothesized that SLC20A2 mutations cause brain calcification most likely through haploinsufficiency. PDGFRB encodes for the platelet-derived growth factor receptor-β (PDGFRβ), a cell-surface tyrosine-kinase (RTK) receptor that regulates cell proliferation, migration, survival and differentiation. PDGFB encodes for the 'platelet-derived growth factor beta' (PDGFβ), the ligand of PDGFRβ. The loss of function of PDGFRβ and PDGFβ could lead to the impairment of the pericytes function and blood brain barrier integrity, causing vascular and perivascular calcium accumulation. SLC20A2 accounts for about 40 % of familial form and 14 % of sporadic cases, while PDGFRB and PDGFB mutations are likely rare. However, approximately 50 % of patients are not genetically defined and there should be at least another causative gene.
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Affiliation(s)
- Ilaria Taglia
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100, Siena, Italy,
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Arts FA, Velghe AI, Stevens M, Renauld JC, Essaghir A, Demoulin JB. Idiopathic basal ganglia calcification-associated PDGFRB mutations impair the receptor signalling. J Cell Mol Med 2014; 19:239-48. [PMID: 25292412 PMCID: PMC4288366 DOI: 10.1111/jcmm.12443] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 08/21/2014] [Indexed: 12/17/2022] Open
Abstract
Platelet-derived growth factors (PDGF) bind to two related receptor tyrosine kinases, which are encoded by the PDGFRA and PDGFRB genes. Recently, heterozygous PDGFRB mutations have been described in patients diagnosed with idiopathic basal ganglia calcification (IBGC or Fahr disease), a rare inherited neurological disorder. The goal of the present study was to determine whether these mutations had a positive or negative impact on the PDGFRB activity. We first showed that the E1071V mutant behaved like wild-type PDGFRB and may represent a polymorphism unrelated to IBGC. In contrast, the L658P mutant had no kinase activity and failed to activate any of the pathways normally stimulated by PDGF. The R987W mutant activated Akt and MAP kinases but did not induce the phosphorylation of signal transducer and activator of transcription 3 (STAT3) after PDGF stimulation. Phosphorylation of phospholipase Cγ was also decreased. Finally, we showed that the R987W mutant was more rapidly degraded upon PDGF binding compared to wild-type PDGFRB. In conclusion, PDGFRB mutations associated with IBGC impair the receptor signalling. PDGFRB loss of function in IBGC is consistent with recently described inactivating mutations in the PDGF-B ligand. These results raise concerns about the long-term safety of PDGF receptor inhibition by drugs such as imatinib.
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Affiliation(s)
- Florence A Arts
- De Duve Institute, Université catholique de Louvain, Brussels, Belgium
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