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Chen Z, Kong Y, Zhang J, Zou WQ, Wu L. Genetic and pathological features encipher the phenotypic heterogeneity of Gerstmann-Sträussler-Scheinker disease. Neurobiol Dis 2024; 195:106497. [PMID: 38583641 DOI: 10.1016/j.nbd.2024.106497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 02/29/2024] [Accepted: 04/04/2024] [Indexed: 04/09/2024] Open
Abstract
OBJECTIVES To elucidate and compare the genetic, clinical, ancillary diagnostic, and pathological characteristics across different Gerstmann-Sträussler-Scheinker disease (GSS) phenotypes and explore the underlying causes of the phenotypic heterogeneities. METHODS The genetic, clinical, ancillary diagnostic, and pathological profiles of GSS patients reported in the literature were obtained and analyzed. Additionally, 3 patients with genetically confirmed GSS from our unit were included. Based on clinical presentation, patients were classified into typical GSS, Creutzfeldt-Jakob disease (CJD)-like GSS, GSS with dementia, and other categories. RESULTS A total of 329 GSS cases were included with a 1.13:1 female-to-male ratio, median onset age 44, and median duration 4 years. Of the 294 categorized patients, 50.7% had typical GSS, 24.8% showed CJD-like GSS, and 16.3% presented with GSS with dementia. Clinical classification varied significantly based on genotype, with P102L more common in typical GSS and A117V prevalent in CJD-like GSS. Polymorphism at codon 129 has no effect on GSS phenotype, but the 129 M allele acts as a protective factor in GSS patients in Asia and North America. Moderate to severe spongiform degeneration and the presence of PK-resistant small fragments migrating at <11 kDa on electrophoretic gels along with PrP27-30 fragments were more prevalent in CJD-like GSS phenotype, while hyperphosphorylated tau protein co-deposition tends to be characteristic of typical GSS and GSS with dementia. CONCLUSION This study reveals GSS's intricate nature, showing significant variations in clinical presentations, diagnostic findings, and pathological features. Mutation sites and pathological changes play crucial roles in determining the GSS clinical heterogeneity.
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Affiliation(s)
- Zhongyun Chen
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yu Kong
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Jing Zhang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Wen-Quan Zou
- Department of Neurology, Institute of Neurology, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China.
| | - Liyong Wu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.
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Chen Z, Chu M, Liu L, Zhang J, Kong Y, Xie K, Cui Y, Ye H, Li J, Wang L, Wu L. Genetic prion diseases presenting as frontotemporal dementia: clinical features and diagnostic challenge. Alzheimers Res Ther 2022; 14:90. [PMID: 35768878 PMCID: PMC9245249 DOI: 10.1186/s13195-022-01033-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 06/22/2022] [Indexed: 11/10/2022]
Abstract
Abstract
Background
To elucidate the clinical and ancillary features of genetic prion diseases (gPrDs) presenting with frontotemporal dementia (FTD) to aid early identification.
Methods
Global data of gPrDs presenting with FTD caused by prion protein gene mutations were collected from literature review and our records. Fifty-one cases of typical FTD and 136 cases of prion diseases admitted to our institution were included as controls. Clinical and ancillary data of the different groups were compared.
Results
Forty-nine cases of gPrDs presenting with FTD were identified. Compared to FTD or prion diseases, gPrDs presenting with FTD were characterized by earlier onset age (median 45 vs. 61/60 years, P < 0.001, P < 0.001) and higher incidence of positive family history (81.6% vs. 27.5/13.2%, P < 0.001, P < 0.001). Furthermore, GPrDs presenting with FTD exhibited shorter duration (median 5 vs. 8 years) and a higher rate of parkinsonism (63.7% vs. 9.8%, P < 0.001), pyramidal signs (39.1% vs. 7.8%, P = 0.001), mutism (35.9% vs. 0%, P < 0.001), seizures (25.8% vs. 0%, P < 0.001), myoclonus (22.5% vs. 0%, P < 0.001), and hyperintensity on MRI (25.0% vs. 0, P < 0.001) compared to FTD. Compared to prion diseases, gPrDs presenting with FTD had a longer duration of symptoms (median 5 vs. 1.1 years, P < 0.001), higher rates of frontotemporal atrophy (89.7% vs. 3.3%, P < 0.001), lower rates of periodic short-wave complexes on EEG (0% vs. 30.3%, P = 0.001), and hyperintensity on MRI (25.0% vs. 83.0%, P < 0.001). The frequency of codon 129 Val allele in gPrDs presenting with FTD was significantly higher than that reported in the literature for gPrDs in the Caucasian and East Asian populations (33.3% vs. 19.2%/8.0%, P = 0.005, P < 0.001).
Conclusions
GPrDs presenting with FTD are characterized by early-onset, high incidence of positive family history, high frequency of the Val allele at codon 129, overlapping symptoms with prion disease and FTD, and ancillary features closer to FTD. PRNP mutations may be a rare cause in the FTD spectrum, and PRNP genotyping should be considered in patients with these features.
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Chen Z, Ma J, Liu L, Liu S, Zhang J, Chu M, Wang Z, Chan P, Wu L. Alterations of Striatal Subregions in a Prion Protein Gene V180I Mutation Carrier Presented as Frontotemporal Dementia With Parkinsonism. Front Aging Neurosci 2022; 14:830602. [PMID: 35493933 PMCID: PMC9053668 DOI: 10.3389/fnagi.2022.830602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/18/2022] [Indexed: 11/13/2022] Open
Abstract
Objective To explore the roles of striatal subdivisions in the pathogenesis of frontotemporal dementia with parkinsonism (FTDP) in a patient resulting from prion protein gene (PRNP) mutation. Methods This patient received clinical interviews and underwent neuropsychological assessments, genetic testing, [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET)/MRI, and [18F]-dihydrotetrabenazine positron emission tomography ([18F]-DTBZ PET)/CT. Region-of-interest analysis was conducted concerning metabolism, and dopamine transport function between this patient and 12 controls, focusing on the striatum subregions according to the Oxford-GSK-Imanova Striatal Connectivity Atlas. Results A 64-year-old man initially presented with symptoms of motor dysfunction and subsequently behavioral and personality changes. FTDP was initially suspected. Sequence analysis disclosed a valine to isoleucine at codon 180 in PRNP. Compared to controls, this patient had a severe reduction (> 2SD) of standard uptake value ratio (SUVR) in the limbic and executive subregions but relative retention of metabolism in rostral motor and caudal motor subregions using [18F]-FDG PET/MRI, and the SUVR decreased significantly across the striatal in [18F]-DTBZ PET/CT, especially in the rostral motor and caudal motor subregions. Conclusion The alteration of frontal striatal loops may be involved in cognitive impairment in FTDP, and the development of parkinsonism in FTDP may be primarily due to the involvement of the presynaptic nigrostriatal loops in PRNP V180I mutation.
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Affiliation(s)
- Zhongyun Chen
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Jinghong Ma
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Li Liu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Shuying Liu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Jing Zhang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Min Chu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Zhen Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Piu Chan
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Liyong Wu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Diseases, Beijing, China
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Legname G, Scialò C. On the role of the cellular prion protein in the uptake and signaling of pathological aggregates in neurodegenerative diseases. Prion 2021; 14:257-270. [PMID: 33345731 PMCID: PMC7757855 DOI: 10.1080/19336896.2020.1854034] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Neurodegenerative disorders are associated with intra- or extra-cellular deposition of aggregates of misfolded insoluble proteins. These deposits composed of tau, amyloid-β or α-synuclein spread from cell to cell, in a prion-like manner. Novel evidence suggests that the circulating soluble oligomeric species of these misfolded proteins could play a major role in pathology, while insoluble aggregates would represent their protective less toxic counterparts. Recent convincing data support the proposition that the cellular prion protein, PrPC, act as a toxicity-inducing receptor for amyloid-β oligomers. As a consequence, several studies focused their investigations to the role played by PrPC in binding other protein aggregates, such as tau and α-synuclein, for its possible common role in mediating toxic signalling. The biological relevance of PrPC as key ligand and potential mediator of toxicity for multiple proteinaceous aggregated species, prions or PrPSc included, could lead to relevant therapeutic implications. Here we describe the structure of PrPC and the proposed interplay with its pathological counterpart PrPSc and then we recapitulate the most recent findings regarding the role of PrPC in the interaction with aggregated forms of other neurodegeneration-associated proteins.
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Affiliation(s)
- Giuseppe Legname
- Department of Neuroscience, Laboratory of Prion Biology, Scuola Internazionale Superiore Di Studi Avanzati (SISSA) , Trieste, Italy
| | - Carlo Scialò
- Department of Neuroscience, Laboratory of Prion Biology, Scuola Internazionale Superiore Di Studi Avanzati (SISSA) , Trieste, Italy
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Cellular Prion Protein (PrPc): Putative Interacting Partners and Consequences of the Interaction. Int J Mol Sci 2020; 21:ijms21197058. [PMID: 32992764 PMCID: PMC7583789 DOI: 10.3390/ijms21197058] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/20/2020] [Accepted: 09/23/2020] [Indexed: 02/08/2023] Open
Abstract
Cellular prion protein (PrPc) is a small glycosylphosphatidylinositol (GPI) anchored protein most abundantly found in the outer leaflet of the plasma membrane (PM) in the central nervous system (CNS). PrPc misfolding causes neurodegenerative prion diseases in the CNS. PrPc interacts with a wide range of protein partners because of the intrinsically disordered nature of the protein’s N-terminus. Numerous studies have attempted to decipher the physiological role of the prion protein by searching for proteins which interact with PrPc. Biochemical characteristics and biological functions both appear to be affected by interacting protein partners. The key challenge in identifying a potential interacting partner is to demonstrate that binding to a specific ligand is necessary for cellular physiological function or malfunction. In this review, we have summarized the intracellular and extracellular interacting partners of PrPc and potential consequences of their binding. We also briefly describe prion disease-related mutations at the end of this review.
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Scialò C, Legname G. The role of the cellular prion protein in the uptake and toxic signaling of pathological neurodegenerative aggregates. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 175:297-323. [PMID: 32958237 DOI: 10.1016/bs.pmbts.2020.08.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Neurodegenerative disorders are invariably associated with intra- or extra-cellular deposition of aggregates composed of misfolded insoluble proteins. These deposits composed of tau, amyloid-β or α-synuclein spread from cell to cell, in a prion-like manner. Emerging evidence suggests that the circulating soluble species of these misfolded proteins (usually referred as oligomers) could play a major role in pathology, while insoluble aggregates would represent their protective less toxic counterparts. Convincing data support the hypothesis that the cellular prion protein, PrPC, act as a toxicity-transducing receptor for amyloid-β oligomers. As a consequence, several studies extended investigations to the role played by PrPC in binding aggregates of proteins other than Aβ, such as tau and α-synuclein, for its possible common role in mediating toxic signaling. A better characterization of the biological relevance of PrPC as key ligand and potential mediator of toxicity for multiple proteinaceous aggregated species, prions or PrPSc included, would bring relevant therapeutic implications. Here we will first describe the structure of the prion protein and the hypothesized interplay with its pathological counterpart PrPSc and then we will recapitulate the most relevant discoveries regarding the role of PrPC in the interaction with aggregated forms of other neurodegeneration-associated proteins.
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Affiliation(s)
- Carlo Scialò
- Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore Di Studi Avanzati (SISSA), Trieste, Italy
| | - Giuseppe Legname
- Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore Di Studi Avanzati (SISSA), Trieste, Italy.
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7
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Bagyinszky E, Yang Y, Giau VV, Youn YC, An SSA, Kim S. Novel prion mutation (p.Tyr225Cys) in a Korean patient with atypical Creutzfeldt-Jakob disease. Clin Interv Aging 2019; 14:1387-1397. [PMID: 31447551 PMCID: PMC6683949 DOI: 10.2147/cia.s210909] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 07/04/2019] [Indexed: 02/06/2023] Open
Abstract
Background: A novel prion variant, PRNP p.Tyr225Cys (c.674A>G; p.Y225C), was identified in an atypical Creutzfeldt–Jakob disease (CJD) patient. The patient had a 5-year history of progressive cognitive impairment with speech and gait disturbances. From the basic neurological examination at his first hospital visit, rigidity and myoclonic jerks in all limbs were observed without focal weakness. Electroencephalogram showed the diffuse slow continuous delta activity in the bilateral cerebral hemisphere. Magnetic resonance imaging revealed abnormalities in the brain, such as cortical signal changes and edema in the frontotemporoparietal lobes and the basal ganglia. Cerebrospinal fluid 14–3-3 protein analysis showed a weakly positive signal. Family history remained unclear, but the patient’s mother and sister were diagnosed with cognitive impairment but both refused genetic testing. Methods: Targeted next generation sequencing (NGS) was performed on 50 genes, involved in different neurodegeneratives diseases, such as Alzheimer's, Parkinson's, frontotemporal dementia or prion diseases. In silico analyses and structure predictions were performed on the potential patohgenic mutations. Results: NGS and standard sequencing revealed the novel PRNP p.Tyr225Cys mutation in the patient. Structure predictions revealed that this may make the helix more flexible. In addition, the extra cysteine residue in TM-III of prion protein may result in disturbances of natural disulfide bond. Conclusion: Hence, the pathogenicity of PRNP p.Tyr225Cys was not fully confirmed at present, and its penetrance was suggested to be low. However, its possible pathogenic nature in prion diseases cannot be ignored, since Tyr/Cys exchange could disturb the helix dynamics and contribute to conformational alteration and disease progression.
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Affiliation(s)
- Eva Bagyinszky
- Department of Bionano Technology, Gachon University, Sungnam, Korea
| | - YoungSoon Yang
- Department of Neurology, Veteran Health Service Medical Center, Seoul, Korea
| | - Vo Van Giau
- Department of Bionano Technology, Gachon University, Sungnam, Korea
| | - Young Chul Youn
- Department of Neurology, Chungang University Hospital, Chungang University, Seoul, Korea
| | - Seong Soo A An
- Department of Bionano Technology, Gachon University, Sungnam, Korea
| | - SangYun Kim
- Department of Neurology, Seoul National University College of Medicine Seoul National University Bundang Hospital, Sungnam, Korea
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8
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Bernardi L, Bruni AC. Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review. Int J Mol Sci 2019; 20:E3606. [PMID: 31340582 PMCID: PMC6678283 DOI: 10.3390/ijms20143606] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 07/07/2019] [Accepted: 07/15/2019] [Indexed: 12/21/2022] Open
Abstract
Inherited mutations in the Prion protein (PrP), encoded by the PRNP gene, have been associated with autosomal dominant neurodegenerative disorders, such as Creutzfeldt-Jacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI). Notably, PRNP mutations have also been described in clinical pictures resembling other neurodegenerative diseases, such as frontotemporal dementia. Regarding the pathogenesis, it has been observed that these point mutations are located in the C-terminal region of the PRNP gene and, currently, the potential significance of the N-terminal domain has largely been underestimated. The purpose of this report is to review and provide current insights into the pathogenic mechanisms of PRNP mutations, emphasizing the differences between the C- and N-terminal regions and focusing, in particular, on the lesser-known flexible N-terminal, for which recent biophysical evidence has revealed a physical interaction with the globular C-terminal domain of the cellular prion protein (PrPC).
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Affiliation(s)
- Livia Bernardi
- Regional Neurogenetic Centre, ASP Catanzaro, 88046 Lamezia Terme (CZ), Italy
| | - Amalia C Bruni
- Regional Neurogenetic Centre, ASP Catanzaro, 88046 Lamezia Terme (CZ), Italy.
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Zhao MM, Feng LS, Hou S, Shen PP, Cui L, Feng JC. Gerstmann-Sträussler-Scheinker disease: A case report. World J Clin Cases 2019; 7:389-395. [PMID: 30746381 PMCID: PMC6369391 DOI: 10.12998/wjcc.v7.i3.389] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/24/2018] [Accepted: 12/30/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gerstmann-Sträussler-Scheinker (GSS) disease is an inherited prion disease that is clinically characterized by the early onset of progressive cerebellar ataxia. The incidence of GSS is extremely low and it is particularly rare in China. Therefore, clinicians may easily confuse this disease with other diseases that also cause ataxia, resulting in its under-diagnosis or misdiagnosis.
CASE SUMMARY Here, we report the first case of genetically diagnosed GSS disease in Northeast China. The patient exhibited typical ataxia and dysarthria 2.5 years after symptom onset. However, magnetic resonance imaging of the brain and spinal cord revealed a normal anatomy. Screening results for the spinocerebellar ataxia gene were also negative. We thus proposed to expand the scope of genetic screening to include over 200 mutations that can cause ataxia. A final diagnosis of GSS was presented and the patient was followed for more than 3.5 years, during which we noted imaging abnormalities. The patient gradually exhibited decorticate posturing and convulsions. We recommended administration of oral sodium valproate, which resolved the convulsions.
CONCLUSION Patients with inherited ataxia should be considered for a diagnosis of GSS via genetic testing at an early disease stage.
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Affiliation(s)
- Ming-Ming Zhao
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Liang-Shu Feng
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Shuai Hou
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Ping-Ping Shen
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li Cui
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jia-Chun Feng
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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10
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Abstract
Genetic prion diseases (gPrDs) caused by mutations in the prion protein gene (PRNP) have been classified as genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, or fatal familial insomnia. Mutations in PRNP can be missense, nonsense, and/or octapeptide repeat insertions or, possibly, deletions. These mutations can produce diverse clinical features. They may also show varying ancillary testing results and neuropathological findings. Although the majority of gPrDs have a rapid progression with a short survival time of a few months, many also present as ataxic or parkinsonian disorders, which have a slower decline over a few to several years. A few very rare mutations manifest as neuropsychiatric disorders, with systemic symptoms that include gastrointestinal disorders and neuropathy; these forms can progress over years to decades. In this review, we classify gPrDs as rapid, slow, or mixed types based on their typical rate of progression and duration, and we review the broad spectrum of phenotypes manifested by these diseases.
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Affiliation(s)
- Mee-Ohk Kim
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
| | - Leonel T Takada
- Cognitive and Behavioral Neurology Unit, Department of Neurology, University of São Paulo, São Paulo, 05403-900, Brazil
| | - Katherine Wong
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
| | - Sven A Forner
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
| | - Michael D Geschwind
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
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Matamoros-Angles A, Gayosso LM, Richaud-Patin Y, di Domenico A, Vergara C, Hervera A, Sousa A, Fernández-Borges N, Consiglio A, Gavín R, López de Maturana R, Ferrer I, López de Munain A, Raya Á, Castilla J, Sánchez-Pernaute R, Del Río JA. iPS Cell Cultures from a Gerstmann-Sträussler-Scheinker Patient with the Y218N PRNP Mutation Recapitulate tau Pathology. Mol Neurobiol 2018; 55:3033-3048. [PMID: 28466265 PMCID: PMC5842509 DOI: 10.1007/s12035-017-0506-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 03/21/2017] [Indexed: 01/20/2023]
Abstract
Gerstmann-Sträussler-Scheinker (GSS) syndrome is a fatal autosomal dominant neurodegenerative prionopathy clinically characterized by ataxia, spastic paraparesis, extrapyramidal signs and dementia. In some GSS familiar cases carrying point mutations in the PRNP gene, patients also showed comorbid tauopathy leading to mixed pathologies. In this study we developed an induced pluripotent stem (iPS) cell model derived from fibroblasts of a GSS patient harboring the Y218N PRNP mutation, as well as an age-matched healthy control. This particular PRNP mutation is unique with very few described cases. One of the cases presented neurofibrillary degeneration with relevant Tau hyperphosphorylation. Y218N iPS-derived cultures showed relevant astrogliosis, increased phospho-Tau, altered microtubule-associated transport and cell death. However, they failed to generate proteinase K-resistant prion. In this study we set out to test, for the first time, whether iPS cell-derived neurons could be used to investigate the appearance of disease-related phenotypes (i.e, tauopathy) identified in the GSS patient.
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Affiliation(s)
- Andreu Matamoros-Angles
- Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Baldiri Reixac 15-21, E-08028, Barcelona, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - Lucía Mayela Gayosso
- Stem cells and neural repair laboratory, Fundación Inbiomed, San Sebastian, Gipuzkoa, Spain
- Proteomics unit (Prion lab), CIC bioGUNE, Parque tecnológico de Bizkaia, 48160, Derio, Bizkaia, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia, Spain
| | - Yvonne Richaud-Patin
- Centre de Medicina Regenerativa de Barcelona, c/ Dr. Aiguader 88, 08003, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Madrid, Spain
| | - Angelique di Domenico
- Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain
- Dept. Patologia i Terapèutica Experimental, Universitat de Barcelona, Barcelona, Spain
| | - Cristina Vergara
- Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Baldiri Reixac 15-21, E-08028, Barcelona, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
- Laboratory of Histology, Neuroanatomy and Neuropathology (CP 620), ULB Neuroscience Institute. Université Libre de Bruxelles, Faculty of Medicine, Brussels, Belgium
| | - Arnau Hervera
- Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Baldiri Reixac 15-21, E-08028, Barcelona, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - Amaya Sousa
- Stem cells and neural repair laboratory, Fundación Inbiomed, San Sebastian, Gipuzkoa, Spain
| | - Natalia Fernández-Borges
- Proteomics unit (Prion lab), CIC bioGUNE, Parque tecnológico de Bizkaia, 48160, Derio, Bizkaia, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia, Spain
- CISA-INIA, Center for Animal Health Research, Madrid, Spain
| | - Antonella Consiglio
- Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain
- Dept. Patologia i Terapèutica Experimental, Universitat de Barcelona, Barcelona, Spain
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Rosalina Gavín
- Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Baldiri Reixac 15-21, E-08028, Barcelona, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | | | - Isidro Ferrer
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
- Dept. Patologia i Terapèutica Experimental, Universitat de Barcelona, Barcelona, Spain
| | - Adolfo López de Munain
- Instituto Biodonostia-Hospital Universitario Donostia, San Sebastian, Gipuzkoa, Spain
- Neurosciences Department, University of the Basque Country UPV-EHU, Bilbao, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), San Sebastian, Gipuzkoa, Spain
| | - Ángel Raya
- Centre de Medicina Regenerativa de Barcelona, c/ Dr. Aiguader 88, 08003, Barcelona, Spain.
- Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Madrid, Spain.
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
| | - Joaquín Castilla
- Proteomics unit (Prion lab), CIC bioGUNE, Parque tecnológico de Bizkaia, 48160, Derio, Bizkaia, Spain.
- IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia, Spain.
| | - Rosario Sánchez-Pernaute
- Stem cells and neural repair laboratory, Fundación Inbiomed, San Sebastian, Gipuzkoa, Spain.
- Andalusian Initiative for Advanced Therapies, Junta de Andalusia, Seville, Spain.
| | - José Antonio Del Río
- Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Baldiri Reixac 15-21, E-08028, Barcelona, Spain.
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain.
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain.
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12
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Abstract
Several studies have indicated that certain misfolded amyloids composed of tau, β-amyloid or α-synuclein can be transferred from cell to cell, suggesting the contribution of mechanisms reminiscent of those by which infective prions spread through the brain. This process of a 'prion-like' spreading between cells is also relevant as a novel putative therapeutic target that could block the spreading of proteinaceous aggregates throughout the brain which may underlie the progressive nature of neurodegenerative diseases. The relevance of β-amyloid oligomers and cellular prion protein (PrPC) binding has been a focus of interest in Alzheimer's disease (AD). At the molecular level, β-amyloid/PrPC interaction takes place in two differently charged clusters of PrPC. In addition to β-amyloid, participation of PrPC in α-synuclein binding and brain spreading also appears to be relevant in α-synucleopathies. This review summarizes current knowledge about PrPC as a putative receptor for amyloid proteins and the physiological consequences of these interactions.
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Affiliation(s)
- José A Del Río
- Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain; Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain; Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain; Institute of Neuroscience, University of Barcelona, Barcelona, Spain.
| | - Isidre Ferrer
- Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain; Institute of Neuroscience, University of Barcelona, Barcelona, Spain; Department of Pathology and Experimental Therapeutics, University of Barcelona, Hospitalet de Llobregat, Spain; Senior Consultant Neuropathology, Service of Pathology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.
| | - Rosalina Gavín
- Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain; Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain; Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain; Institute of Neuroscience, University of Barcelona, Barcelona, Spain
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13
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Bagyinszky E, Giau VV, Youn YC, An SSA, Kim S. Characterization of mutations in PRNP (prion) gene and their possible roles in neurodegenerative diseases. Neuropsychiatr Dis Treat 2018; 14:2067-2085. [PMID: 30147320 PMCID: PMC6097508 DOI: 10.2147/ndt.s165445] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Abnormal prion proteins are responsible for several fatal neurodegenerative diseases in humans and in animals, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. Genetics is important in prion diseases, but in the most cases, cause of diseases remained unknown. Several mutations were found to be causative for prion disorders, and the effect of mutations may be heterogeneous. In addition, different prion mutations were suggested to play a possible role in additional phenotypes, such as Alzheimer's type pathology, spongiform encephalopathy, or frontotemporal dementia. Pathogenic nature of several prion mutations remained unclear, such as M129V and E219K. These two polymorphic sites were suggested as either risk factors for different disorders, such as Alzheimer's disease (AD), variant CJD, or protease-sensitive prionopathy, and they can also be disease-modifying factors. Pathological overlap may also be possible with AD or progressive dementia, and several patients with prion mutations were initially diagnosed with AD. This review also introduces briefly the diagnosis of prion diseases and the issues with their diagnosis. Since prion diseases have quite heterogeneous phenotypes, a complex analysis, a combination of genetic screening, cerebrospinal fluid biomarker analysis and imaging technologies could improve the early disease diagnosis.
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Affiliation(s)
- Eva Bagyinszky
- Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, Gyeonggi-do, South Korea,
| | - Vo Van Giau
- Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, Gyeonggi-do, South Korea,
| | - Young Chul Youn
- Department of Neurology, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Seong Soo A An
- Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, Gyeonggi-do, South Korea,
| | - SangYun Kim
- Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, South Korea
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14
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Takada LT, Kim MO, Metcalf S, Gala II, Geschwind MD. Prion disease. HANDBOOK OF CLINICAL NEUROLOGY 2018; 148:441-464. [DOI: 10.1016/b978-0-444-64076-5.00029-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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15
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Takada LT, Kim MO, Cleveland RW, Wong K, Forner SA, Gala II, Fong JC, Geschwind MD. Genetic prion disease: Experience of a rapidly progressive dementia center in the United States and a review of the literature. Am J Med Genet B Neuropsychiatr Genet 2017; 174:36-69. [PMID: 27943639 PMCID: PMC7207989 DOI: 10.1002/ajmg.b.32505] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 10/04/2016] [Indexed: 12/21/2022]
Abstract
Although prion diseases are generally thought to present as rapidly progressive dementias with survival of only a few months, the phenotypic spectrum for genetic prion diseases (gPrDs) is much broader. The majority have a rapid decline with short survival, but many patients with gPrDs present as slowly progressive ataxic or parkinsonian disorders with progression over a few to several years. A few very rare mutations even present as neuropsychiatric disorders, sometimes with systemic symptoms such as gastrointestinal disorders and neuropathy, progressing over years to decades. gPrDs are caused by mutations in the prion protein gene (PRNP), and have been historically classified based on their clinicopathological features as genetic Jakob-Creutzfeldt disease (gJCD), Gerstmann-Sträussler-Scheinker (GSS), or Fatal Familial Insomnia (FFI). Mutations in PRNP can be missense, nonsense, and octapeptide repeat insertions or a deletion, and present with diverse clinical features, sensitivities of ancillary testing, and neuropathological findings. We present the UCSF gPrD cohort, including 129 symptomatic patients referred to and/or seen at UCSF between 2001 and 2016, and compare the clinical features of the gPrDs from 22 mutations identified in our cohort with data from the literature, as well as perform a literature review on most other mutations not represented in our cohort. E200K is the most common mutation worldwide, is associated with gJCD, and was the most common in the UCSF cohort. Among the GSS-associated mutations, P102L is the most commonly reported and was also the most common at UCSF. We also had several octapeptide repeat insertions (OPRI), a rare nonsense mutation (Q160X), and three novel mutations (K194E, E200G, and A224V) in our UCSF cohort. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Leonel T. Takada
- Cognitive and Behavioral Neurology Unit, Department of Neurology, University of São Paulo, São Paulo, Brazil
| | - Mee-Ohk Kim
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94107
| | - Ross W. Cleveland
- Department of Pediatrics, The University of Vermont Children’s Hospital, University of Vermont, Burlington, VT 05401
| | - Katherine Wong
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94107
| | - Sven A. Forner
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94107
| | - Ignacio Illán Gala
- Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Jamie C. Fong
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94107
| | - Michael D. Geschwind
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94107
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16
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Riudavets MA, Sraka MA, Schultz M, Rojas E, Martinetto H, Begué C, Noher de Halac I, Poleggi A, Equestre M, Pocchiari M, Sevlever G, Taratuto AL. Gerstmann-Sträussler-Scheinker syndrome with variable phenotype in a new kindred with PRNP-P102L mutation. Brain Pathol 2013; 24:142-7. [PMID: 23944754 DOI: 10.1111/bpa.12083] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Accepted: 08/08/2013] [Indexed: 12/15/2022] Open
Abstract
Gerstmann-Sträussler-Scheinker syndrome (GSS) is a dominantly inherited disorder belonging to the group of transmissible human spongiform encephalopathies or prion diseases. Several families affected by GSS with patients carrying mutations in the prion protein gene have been described worldwide. We report clinical, genealogical, neuropathology and molecular study results from two members of the first Argentine kindred affected by GSS. Both family members presented a frontotemporal-like syndrome, one with and the other without ataxia, with different lesions on neuropathology. A Pro to Leu point mutation at codon 102 (P102L) of the prion protein gene was detected in one of the subjects studied. The pathogenic basis of phenotypic variability observed in this family remains unclear, but resembles that observed in other P102L GSS patients from the same family.
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Affiliation(s)
- Miguel A Riudavets
- Department of Neuropathology, Institute for Neurological Research, FLENI, Buenos Aires, Argentina
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Jahandideh S, Zhi D. Systematic investigation of predicted effect of nonsynonymous SNPs in human prion protein gene: a molecular modeling and molecular dynamics study. J Biomol Struct Dyn 2013; 32:289-300. [PMID: 23527686 DOI: 10.1080/07391102.2012.763216] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nonsynonymous mutations in the human prion protein (HuPrP) gene contribute to the conversion of HuPrP(C) to HuPrP(Sc) and amyloid formation which in turn leads to prion diseases such as familial Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker disease. In order to better understand and predict the role of HuPrP mutations, we developed the following procedure: first, we consulted the Human Genome Variation database and dbSNP databases, and we reviewed literature for the retrieval of aggregation-related nsSNPs of the HuPrP gene. Next, we used three different methods - Polymorphism Phenotyping (PolyPhen), PANTHER, and Auto-Mute - to predict the effect of nsSNPs on the phenotype. We compared the predictions against experimentally reported effects of these nsSNPs to evaluate the accuracy of the three methods: PolyPhen predicted 17 out of 22 nsSNPs as "probably damaging" or "possibly damaging"; PANTHER predicted 8 out of 22 nsSNPs as "Deleterious"; and Auto-Mute predicted 9 out of 20 nsSNPs as "Disease". Finally, structural analyses of the native protein against mutated models were investigated using molecular modeling and molecular dynamics (MD) simulation methods. In addition to comparing predictor methods, our results show the applicability of our procedure for the prediction of damaging nsSNPs. Our study also elucidates the obvious relationship between predicted values of aggregation-related nsSNPs in HuPrP gene and molecular modeling and MD simulations results. In conclusion, this procedure would enable researchers to select outstanding candidates for extensive MD simulations in order to decipher more details of HuPrP aggregation. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:34.
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Affiliation(s)
- Samad Jahandideh
- a Section on Statistical Genetics, Department of Biostatistics , School of Public Health, University of Alabama at Birmingham , Birmingham , AL , 35294 , USA
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18
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Prion diseases. Neurogenetics 2012. [DOI: 10.1017/cbo9781139087711.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Behmard E, Abdolmaleki P, Asadabadi EB, Jahandideh S. Prevalent Mutations of Human Prion Protein: A Molecular Modeling and Molecular Dynamics Study. J Biomol Struct Dyn 2011; 29:379-89. [DOI: 10.1080/07391102.2011.10507392] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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20
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A NovelPRNP Y218NMutation in Gerstmann-Sträussler-Scheinker Disease With Neurofibrillary Degeneration. J Neuropathol Exp Neurol 2010; 69:789-800. [DOI: 10.1097/nen.0b013e3181e85737] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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21
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Jansen C, Parchi P, Capellari S, Vermeij AJ, Corrado P, Baas F, Strammiello R, van Gool WA, van Swieten JC, Rozemuller AJM. Prion protein amyloidosis with divergent phenotype associated with two novel nonsense mutations in PRNP. Acta Neuropathol 2010; 119:189-97. [PMID: 19911184 PMCID: PMC2808512 DOI: 10.1007/s00401-009-0609-x] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2009] [Revised: 10/31/2009] [Accepted: 10/31/2009] [Indexed: 12/11/2022]
Abstract
Stop codon mutations in the gene encoding the prion protein (PRNP) are very rare and have thus far only been described in two patients with prion protein cerebral amyloid angiopathy (PrP-CAA). In this report, we describe the clinical, histopathological and pathological prion protein (PrP(Sc)) characteristics of two Dutch patients carrying novel adjacent stop codon mutations in the C-terminal part of PRNP, resulting in either case in hereditary prion protein amyloidoses, but with strikingly different clinicopathological phenotypes. The patient with the shortest disease duration (27 months) carried a Y226X mutation and showed PrP-CAA without any neurofibrillary lesions, whereas the patient with the longest disease duration (72 months) had a Q227X mutation and showed an unusual Gerstmann-Sträussler-Scheinker disease phenotype with numerous cerebral multicentric amyloid plaques and severe neurofibrillary lesions without PrP-CAA. Western blot analysis in the patient with the Q227X mutation demonstrated the presence of a 7 kDa unglycosylated PrP(Sc) fragment truncated at both the N- and C-terminal ends. Our observations expand the spectrum of clinicopathological phenotypes associated with PRNP mutations and show that a single tyrosine residue difference in the PrP C-terminus may significantly affect the site of amyloid deposition and the overall phenotypic expression of the prion disease. Furthermore, it confirms that the absence of the glycosylphosphatidylinositol anchor in PrP predisposes to amyloid plaque formation.
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Affiliation(s)
- Casper Jansen
- Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.
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Atypical frontotemporal dementia as a new clinical phenotype of Gerstmann-Straussler-Scheinker disease with the PrP-P102L mutation. Description of a previously unreported Italian family. Neurol Sci 2008; 29:405-10. [DOI: 10.1007/s10072-008-1025-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2008] [Accepted: 08/18/2008] [Indexed: 12/11/2022]
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23
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Zheng L, Longfei J, Jing Y, Xinqing Z, Haiqing S, Haiyan L, Fen W, Xiumin D, Jianping J. PRNP mutations in a series of apparently sporadic neurodegenerative dementias in China. Am J Med Genet B Neuropsychiatr Genet 2008; 147B:938-44. [PMID: 18425766 DOI: 10.1002/ajmg.b.30761] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Mutations in prion protein gene (PRNP) may lead to genetic prion disease, which usually has a broad range of phenotypic presentations that overlap with other neurodegenerative dementias. In this study, we screened the PRNP gene to evaluate the frequency of PRNP mutations and their correlations with clinical phenotype in 185 sporadic neurodegenerative dementia cases and 310 control subjects. Samples of DNA from each subject underwent polymerase chain reaction (PCR) amplification and direct sequencing of PRNP. The clinical characteristics of patients carrying PRNP mutations were detailed. We identified five different PRNP mutations in five patients, of which three were novel (S97N, F198V, and R208C) and two were known (D178N-129M and M232R). The rate of PRNP mutation was 2.70% in our sample. Though future studies confirming the correlation between PRNP mutations and clinical phenotype need to be undertaken, PRNP genotyping may be a valuable tool to differentiate between prion disease and other neurodegenerative dementias.
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Affiliation(s)
- Liu Zheng
- Department of Neurology, Xuanwu Hospital, Capital University of Medical Sciences, Beijing, China
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