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Dzichenka Y, Shapira M, Sachanka A, Cherkesova T, Shchur V, Grbović L, Pavlović K, Vasiljević B, Savić M, Nikolić A, Oklješa A, Ajduković J, Kuzminac I, Yantsevich A, Usanov S, Jovanović-Šanta S. Discovery of the potential of cholesterol-lowering human CYP7 enzymes as biocatalysts for the production of C7 hydroxylated steroids. Biophys Chem 2025; 319:107393. [PMID: 39908942 DOI: 10.1016/j.bpc.2025.107393] [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: 11/01/2024] [Revised: 01/14/2025] [Accepted: 01/24/2025] [Indexed: 02/07/2025]
Abstract
Steroidal C7 alcohols and their esters are perspective agents in drug discovery. In addition, hydroxylation at C7 position could allow further modification of steroidal moiety. Such transformation is performed easily by the enzymes. Human steroid 7α-hydroxylases CYP7A1 and CYP7B1 are key enzymes taking part in the biotransformation of cholestanes, androstanes, pregnanes. In the article, we are focusing on the results of in vitro screening of a library of modified steroids toward CYP7 enzymes. A couple of compounds were found to express the affinity for binding to the enzymes, comparable with corresponding values for CYP7 natural ligands. Among them are 17-substituted androstane derivatives with N-containing pyridine ring and enone derivative of lithocholic acid, which bound by human CYP7A1, and D-seco and C16 oxime androstanes, which were identified as novel CYP7B1 ligands. Screening results revealed that both enzymes bind with high affinity a well-known drug abiraterone: in the case of CYP7A1 substrate-like binding mode was detected, with the formation of monohydroxylated product, while in case of CYP7B1 inhibitor-like binding was observed. Since CYP7 enzymes convert some of the studied compounds into their 7-hydroxy derivatives, potential of these enzymes as perspective regio- and stereoselective biocatalysts for obtaining C7 hydroxylated steroids could be assumed.
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Affiliation(s)
- Yaraslau Dzichenka
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus.
| | - Michail Shapira
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus
| | - Antos Sachanka
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus
| | - Tatsiana Cherkesova
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus
| | - Veronika Shchur
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus
| | - Ljubica Grbović
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Ksenija Pavlović
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Bojana Vasiljević
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia; Institute of Nuclear Sciences Vinča - National Institute of the Republic of Serbia, University of Belgrade, 11001 Belgrade, Serbia
| | - Marina Savić
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Andrea Nikolić
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Aleksandar Oklješa
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Jovana Ajduković
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Ivana Kuzminac
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Aliaksei Yantsevich
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus
| | - Sergey Usanov
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus
| | - Suzana Jovanović-Šanta
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia.
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Pashaei M, Davarzani A, Hajati R, Zamani B, Nafissi S, Larti F, Nilipour Y, Rohani M, Alavi A. Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families. J Neurogenet 2021; 35:84-94. [PMID: 33771085 DOI: 10.1080/01677063.2021.1895146] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder, characterized by lower-limb spasticity and weakness. To date, more than 82 loci/genes (SPG1-SPG82) have been identified that contribute to the cause of HSP. Despite the use of next-generation sequencing-based methods, genetic-analysis has failed in the finding of causative genes in more than 50% of HSP patients, indicating a more significant heterogeneity and absence of a given phenotype-genotype correlation. Here, we performed whole-exome sequencing (WES) to identify HSP-causing genes in three unrelated-Iranian probands. Candidate variants were detected and confirmed in the probands and co-segregated in the family members. The phenotypic data gathered and compared with earlier cases with the same sub-types of disease. Three novel homozygous variants, c.978delT; p.Q327Kfs*39, c.A1208G; p.D403G and c.3811delT; p.S1271Lfs*44, in known HSP-causing genes including ENTPD1, CYP7B1, and ZFYVE26 were identified, respectively. Intra and interfamilial clinical variability were observed among affected individuals. Mutations in CYP7B1 and ZFYVE26 are relatively common causes of HSP and associated with SPG5A and SPG15, respectively. However, mutations in ENTPD1 are related to SPG64 which is an ultra-rare form of HSP. The research affirmed more complexities of phenotypic manifestations and allelic heterogeneity in HSP. Due to these complexities, it is not feasible to show a clear phenotype-genotype correlation in HSP cases. Identification of more families with mutations in HSP-causing genes may help the establishment of this correlation, further understanding of the molecular basis of the disease, and would provide an opportunity for genetic-counseling in these families.
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Affiliation(s)
- Mahdieh Pashaei
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Atefeh Davarzani
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Reza Hajati
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Babak Zamani
- Neurology Department, Firoozgar hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Shahriar Nafissi
- Department of Neurology, Shariati Hospital., Tehran University of Medical Sciences, Tehran, Iran
| | - Farzaneh Larti
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Yalda Nilipour
- Pediatric Pathology Research Center, Research Institute for Children Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Rohani
- Department of Neurology, Hazrat Rasool Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Afagh Alavi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
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Chiang JY, Ferrell JM. Up to date on cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis. LIVER RESEARCH 2020; 4:47-63. [PMID: 34290896 PMCID: PMC8291349 DOI: 10.1016/j.livres.2020.05.001] [Citation(s) in RCA: 157] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cholesterol 7 alpha-hydroxylase (CYP7A1, EC1.14) is the first and rate-limiting enzyme in the classic bile acid synthesis pathway. Much progress has been made in understanding the transcriptional regulation of CYP7A1 gene expression and the underlying molecular mechanisms of bile acid feedback regulation of CYP7A1 and bile acid synthesis in the last three decades. Discovery of bile acid-activated receptors and their roles in the regulation of lipid, glucose and energy metabolism have been translated to the development of bile acid-based drug therapies for the treatment of liver-related metabolic diseases such as alcoholic and non-alcoholic fatty liver diseases, liver cirrhosis, diabetes, obesity and hepatocellular carcinoma. This review will provide an update on the advances in our understanding of the molecular biology and mechanistic insights of the regulation of CYP7A1 in bile acid synthesis in the last 40 years.
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Siow SF, Cameron Smail R, Ng K, Kumar KR, Sue CM. Motor Evoked Potentials in Hereditary Spastic Paraplegia-A Systematic Review. Front Neurol 2019; 10:967. [PMID: 31620065 PMCID: PMC6759520 DOI: 10.3389/fneur.2019.00967] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 08/23/2019] [Indexed: 12/11/2022] Open
Abstract
Background: Hereditary Spastic Paraplegia (HSP) is a slowly progressive neurodegenerative disorder with no disease modifying treatment. Potential therapeutic approaches are emerging and large-scale clinical drug trials for patients with HSP are imminent. A sensitive biomarker to measure the drug efficacy in these trials is required. Motor evoked potentials (MEPs) are a potential biomarker for HSP as they assess the central motor pathways and can be standardized with set protocols and guidelines. Objectives: We performed a systematic review to investigate the utility of MEPs as a diagnostic and disease severity biomarker for HSP. Search Methods: Systematic searches of PubMed, Embase, Medline, and Scopus were performed. Selection Criteria: Studies reporting on central motor conduction time measured with MEPs in adult and pediatric patients with HSP were included. We excluded studies in non-HSP patient cohorts, not in English, not original research, and unpublished journal articles. Data Collection and analysis: Search results were de-duplicated and screened according to the inclusion and exclusion criteria. The included papers were reviewed independently by two reviewers and data was collected on patient cohorts, test methods, results, and study quality. Results were analyzed using descriptive methods. Results: Of the 882 search results, 32 studies were included in the review. The most common finding was absent or prolonged lower limb (LL) central motor conduction time (CMCT) in patients with HSP (78% of patients studied). Quality assessment revealed variability in study methodology and reporting of results. Variations included patient cohorts of various genotypes as well as variations in equipment and techniques used. Aside from CMCT, none of the MEP parameter measures correlated with disease severity and many did not show significant difference between HSP patients and controls. Conclusion: Systematic review of MEP studies in HSP patient cohorts demonstrated mixed findings. Lower limb CMCT was the most promising parameter in terms of differentiating HSP patients from controls, with one study demonstrating a weak correlation with clinical disease severity. It is possible that the lack of consistency in study methodologies and small patient cohorts have contributed to the variable findings. A longitudinal study of MEPs in a large cohort of HSP patients with the same genotype will help clarify the utility of MEPs as a biomarker for disease severity and use in clinical trials.
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Affiliation(s)
- Sue-Faye Siow
- Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia.,Department of Neurology and Neurophysiology, Royal North Shore Hospital, St Leonards, NSW, Australia.,Northern Clinical School, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Ruaridh Cameron Smail
- Department of Neurology and Neurophysiology, Royal North Shore Hospital, St Leonards, NSW, Australia.,Northern Clinical School, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Karl Ng
- Department of Neurology and Neurophysiology, Royal North Shore Hospital, St Leonards, NSW, Australia.,Northern Clinical School, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Kishore R Kumar
- Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia.,Department of Neurology, Concord Hospital, Sydney, NSW, Australia.,Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,Molecular Medicine Laboratory, Concord Hospital, Sydney, NSW, Australia
| | - Carolyn M Sue
- Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia.,Department of Neurology and Neurophysiology, Royal North Shore Hospital, St Leonards, NSW, Australia.,Northern Clinical School, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia
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Beetz C, Khundadze M, Goldberg LV, Hübner CA. Erbliche spastische Spinalparalysen: aktuelle Erkenntnisse und Entwicklungen. MED GENET-BERLIN 2018. [DOI: 10.1007/s11825-018-0196-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Zusammenfassung
Die erblichen spastischen Spinalparalysen („hereditary spastic paraplegias“, HSPs) sind Bewegungsstörungen, die aus der Degeneration der Axone oberer Motoneuronen resultieren. Sie sind klinisch und genetisch sehr heterogen. Der vorliegende Übersichtsartikel fasst aktuelle Strategien zur genetischen Diagnostik der HSPs zusammen, erörtert mögliche Mutationsmechanismen, diskutiert Erklärungen für die klinische Variabilität innerhalb ausgewählter Formen und verweist auf noch ungeklärte und zum Teil wenig beachtete Phänomene. Außerdem wird die Notwendigkeit eines tieferen Verständnisses der zellulären und molekularen Mechanismen für die Entwicklung neuer Therapien dargestellt.
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Affiliation(s)
- Christian Beetz
- Aff1 0000 0000 8517 6224 grid.275559.9 Institut für Klinische Chemie und Laboratoriumsdiagnostik Universitätsklinikum Jena Jena Deutschland
| | - Mukhran Khundadze
- Aff2 0000 0000 8517 6224 grid.275559.9 Institut für Humangenetik Universitätsklinikum Jena Am Klinikum 1 07747 Jena Deutschland
| | - Lisa V. Goldberg
- Aff1 0000 0000 8517 6224 grid.275559.9 Institut für Klinische Chemie und Laboratoriumsdiagnostik Universitätsklinikum Jena Jena Deutschland
| | - Christian A. Hübner
- Aff2 0000 0000 8517 6224 grid.275559.9 Institut für Humangenetik Universitätsklinikum Jena Am Klinikum 1 07747 Jena Deutschland
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Dong EL, Wang C, Wu S, Lu YQ, Lin XH, Su HZ, Zhao M, He J, Ma LX, Wang N, Chen WJ, Lin X. Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China. Mol Neurodegener 2018; 13:36. [PMID: 29980238 PMCID: PMC6035405 DOI: 10.1186/s13024-018-0269-1] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 06/26/2018] [Indexed: 12/17/2022] Open
Abstract
Background Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogenesis in this population. Methods We firstly performed next-generation sequencing targeting 149 genes correlated with HSP in 99 index cases of our cohort. Multiplex ligation-dependent probe amplification testing was further carried out among those patients without known disease-causing gene mutations. We simultaneously performed a retrospective study on the reported patients exhibiting HSP in other Chinese cohorts. All clinical and molecular characterization from above two groups of Chinese HSP patients were analyzed and summarized. Eventually, we further validated the cellular changes in fibroblasts of two major spastic paraplegia (SPG) patients (SPG4 and SPG11) in vitro. Results Most patients of ADHSP (94%) are pure forms, whereas most patients of ARHSP (78%) tend to be complicated forms. In ADHSP, we found that SPG4 (79%) was the most prevalent, followed by SPG3A (11%), SPG6 (4%) and SPG33 (2%). Subtle mutations were the common genetic cause for SPG4 patients and most of them located in AAA cassette domain of spastin protein. In ARHSP, the most common subtype was SPG11 (53%), followed by SPG5 (32%), SPG35 (6%) and SPG46 (3%). Moreover, haplotype analysis showed a unique haplotype was shared in 14 families carrying c.334C > T (p.R112*) mutation in CYP7B1 gene, suggesting the founder effect. Functionally, we observed significantly different patterns of mitochondrial dynamics and network, decreased mitochondrial membrane potential (Δψm), increased reactive oxygen species and reduced ATP content in SPG4 fibroblasts. Moreover, we also found the enlargement of LAMP1-positive organelles and abnormal accumulation of autolysosomes in SPG11 fibroblasts. Conclusions Our study present a comprehensive clinical spectrum and genetic landscape for HSP in China. We have also provided additional evidences for mitochondrial and autolysosomal-mediated pathways in the pathogenesis of HSP. Electronic supplementary material The online version of this article (10.1186/s13024-018-0269-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- En-Lin Dong
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Chong Wang
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Shuang Wu
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Ying-Qian Lu
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Xiao-Hong Lin
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Hui-Zhen Su
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Miao Zhao
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Jin He
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Li-Xiang Ma
- Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ning Wang
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.,Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China
| | - Wan-Jin Chen
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China. .,Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China.
| | - Xiang Lin
- Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
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Starkey NJE, Li Y, Drenkhahn-Weinaug SK, Liu J, Lubahn DB. 27-Hydroxycholesterol Is an Estrogen Receptor β-Selective Negative Allosteric Modifier of 17β-Estradiol Binding. Endocrinology 2018; 159:1972-1981. [PMID: 29579190 PMCID: PMC6693046 DOI: 10.1210/en.2018-00081] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 03/13/2018] [Indexed: 01/23/2023]
Abstract
Estrogens bind to two nuclear estrogen receptor (ER) subtypes, ERα and ERβ, which are expressed in differing amounts in various tissues. The endogenous estrogen, 17β-estradiol (E2), binds to both subtypes with nearly equal affinity and is the prototypical agonist. Selective estrogen receptor modulators (SERMs) may bind to both subtypes with equivalent affinities but have agonist activities in some tissues while having antagonist activities in others. In the present study, we demonstrate that the first reported endogenous SERM, 27-hydroxycholesterol (27-OHC), binds preferentially (>100-fold) to ERβ over ERα. Furthermore, 27-OHC is not able to fully compete with E2 binding, suggesting the two may bind at different sites. We provide an allosteric ternary complex model for the simultaneous binding of 27-OHC and E2 to ERβ, which accurately describes the binding data we have observed. We conclude that 27-OHC is a negative allosteric modifier of E2 binding, with an inhibitor constantof 50 nM and cooperativity factor (α) of 0.036. We also propose an in silico three-dimensional model of the simultaneous binding to guide future experiments. Further study of this unique binding model may allow for the discovery of novel ERβ-selective ligands and potentially explain the lack of effectiveness of ERβ-selective agonists in humans vs preclinical models.
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Affiliation(s)
| | - Yufei Li
- Department of Biochemistry, University of Missouri, Columbia, Missouri
| | - Sara K Drenkhahn-Weinaug
- Department of Biochemistry, University of Missouri, Columbia, Missouri
- Department of Chemistry, Lindenwood University–Belleville, Belleville, Illinois
| | - Jinghua Liu
- Department of Biochemistry, University of Missouri, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Dennis B Lubahn
- Department of Biochemistry, University of Missouri, Columbia, Missouri
- Department of Child Health, University of Missouri, Columbia, Missouri
- Correspondence: Dennis B. Lubahn, PhD, 110A Animal Science Research Center, University of Missouri, Columbia, Missouri 65211. E-mail:
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8
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Schöls L, Rattay TW, Martus P, Meisner C, Baets J, Fischer I, Jägle C, Fraidakis MJ, Martinuzzi A, Saute JA, Scarlato M, Antenora A, Stendel C, Höflinger P, Lourenco CM, Abreu L, Smets K, Paucar M, Deconinck T, Bis DM, Wiethoff S, Bauer P, Arnoldi A, Marques W, Jardim LB, Hauser S, Criscuolo C, Filla A, Züchner S, Bassi MT, Klopstock T, De Jonghe P, Björkhem I, Schüle R. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Brain 2017; 140:3112-3127. [PMID: 29126212 PMCID: PMC5841036 DOI: 10.1093/brain/awx273] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 08/22/2017] [Accepted: 08/26/2017] [Indexed: 12/31/2022] Open
Abstract
Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7α-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683-1113] to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.
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Affiliation(s)
- Ludger Schöls
- Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, 72076 Tübingen, Germany
- German Center of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany
| | - Tim W Rattay
- Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, 72076 Tübingen, Germany
- German Center of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany
| | - Peter Martus
- Institute for Clinical Epidemiology and Applied Biostatistics, Eberhard-Karls-University, 72076 Tübingen, Germany
| | - Christoph Meisner
- Institute for Clinical Epidemiology and Applied Biostatistics, Eberhard-Karls-University, 72076 Tübingen, Germany
| | - Jonathan Baets
- Neurogenetics Group, Center for Molecular Neurology, VIB, 2610 Antwerp, Belgium
- Department of Neurology, Antwerp University Hospital, 2610 Antwerp, Belgium
- Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
| | - Imma Fischer
- Institute for Clinical Epidemiology and Applied Biostatistics, Eberhard-Karls-University, 72076 Tübingen, Germany
| | - Christine Jägle
- Center for Rare Diseases and Institute of Human Genetics and Applied Genomics, Eberhard-Karls-University, 72076 Tübingen, Germany
| | - Matthew J Fraidakis
- Rare Neurological Diseases Unit, Department of Neurology, University Hospital ‘Attikon’, Medical School of the University of Athens, 12462 Athens, Greece
| | - Andrea Martinuzzi
- Scientific Institute IRCCS E. Medea, Conegliano Research Center, 31015 Conegliano, Italy
| | - Jonas Alex Saute
- Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Genetics Identification Laboratory, Hospital de Clínicas de Porto Alegre, 90035 Porto Alegre, Brazil
- Postgraduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), 90040 Porto Alegre, Brazil
| | - Marina Scarlato
- Neurology Department and INSPE, San Raffaele Hospital, 20132 Milan, Italy
| | - Antonella Antenora
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University Naples, 80131 Naples, Italy
| | - Claudia Stendel
- Department of Neurology, Friedrich Baur Institute, Ludwig-Maximilians-University, 80336 Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
| | - Philip Höflinger
- Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, 72076 Tübingen, Germany
- German Center of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany
| | - Charles Marques Lourenco
- Departamento de Neurologia, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, 14049 Ribeirao Preto, Brazil
- Department of Internal Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), 90040 Porto Alegre, Brazil
| | - Lisa Abreu
- John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, 33136 Miami, Florida, USA
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, 33136 Miami, Florida, USA
| | - Katrien Smets
- Neurogenetics Group, Center for Molecular Neurology, VIB, 2610 Antwerp, Belgium
- Department of Neurology, Antwerp University Hospital, 2610 Antwerp, Belgium
- Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
| | - Martin Paucar
- Department of Neurology, Karolinska University Hospital Huddinge and Department of Clinical Neuroscience, Karolinska Institute, 14152 Huddinge, Sweden
| | - Tine Deconinck
- Neurogenetics Group, Center for Molecular Neurology, VIB, 2610 Antwerp, Belgium
- Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
| | - Dana M Bis
- John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, 33136 Miami, Florida, USA
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, 33136 Miami, Florida, USA
| | - Sarah Wiethoff
- Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, 72076 Tübingen, Germany
- German Center of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany
- Institute of Neurology, Queen Square, London WC1N 3BG, UK
| | - Peter Bauer
- Institute of Medical Genetics and Applied Genomics, Eberhard-Karls-University, 72076 Tübingen, Germany
- CENTOGENE AG, 18057 Rostock, Germany
| | - Alessia Arnoldi
- Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, 23842 Bosisio Parini, Italy
| | - Wilson Marques
- Departamento de Neurologia, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, 14049 Ribeirao Preto, Brazil
| | - Laura Bannach Jardim
- Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Genetics Identification Laboratory, Hospital de Clínicas de Porto Alegre, 90035 Porto Alegre, Brazil
- Postgraduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), 90040 Porto Alegre, Brazil
- Department of Internal Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), 90040 Porto Alegre, Brazil
| | - Stefan Hauser
- Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, 72076 Tübingen, Germany
- German Center of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany
| | - Chiara Criscuolo
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University Naples, 80131 Naples, Italy
| | - Alessandro Filla
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University Naples, 80131 Naples, Italy
| | - Stephan Züchner
- John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, 33136 Miami, Florida, USA
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, 33136 Miami, Florida, USA
| | - Maria Teresa Bassi
- Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, 23842 Bosisio Parini, Italy
| | - Thomas Klopstock
- Department of Neurology, Friedrich Baur Institute, Ludwig-Maximilians-University, 80336 Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
| | - Peter De Jonghe
- Neurogenetics Group, Center for Molecular Neurology, VIB, 2610 Antwerp, Belgium
- Department of Neurology, Antwerp University Hospital, 2610 Antwerp, Belgium
- Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
| | - Ingemar Björkhem
- Karolinska University Hospital Huddinge, Karolinska Institute, 14152 Stockholm, Sweden
| | - Rebecca Schüle
- Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, 72076 Tübingen, Germany
- German Center of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany
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Corso G, Dello Russo A, Gelzo M. Liver and the defects of cholesterol and bile acids biosynthesis: Rare disorders many diagnostic pitfalls. World J Gastroenterol 2017; 23:5257-5265. [PMID: 28839426 PMCID: PMC5550775 DOI: 10.3748/wjg.v23.i29.5257] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 05/01/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
In recent decades, biotechnology produced a growth of knowledge on the causes and mechanisms of metabolic diseases that have formed the basis for their study, diagnosis and treatment. Unfortunately, it is well known that the clinical features of metabolic diseases can manifest themselves with very different characteristics and escape early detection. Also, it is well known that the prognosis of many metabolic diseases is excellent if diagnosed and treated early. In this editorial we briefly summarized two groups of inherited metabolic diseases, the defects of cholesterol biosynthesis and those of bile acids. Both groups show variable clinical manifestations but some clinical signs and symptoms are common in both the defects of cholesterol and bile acids. The differential diagnosis can be made analyzing sterol profiles in blood and/or bile acids in blood and urine by chromatographic techniques (GC-MS and LC-MS/MS). Several defects of both biosynthetic pathways are treatable so early diagnosis is crucial. Unfortunately their diagnosis is made too late, due either to the clinical heterogeneity of the syndromes (severe, mild and very mild) that to the scarcity of scientific dissemination of these rare diseases. Therefore, the delay in diagnosis leads the patient to the medical observation when the disease has produced irreversible damages to the body. Here, we highlighted simple clinical and laboratory descriptions that can potentially make you to suspect a defect in cholesterol biosynthesis and/or bile acids, as well, we suggest appropriate request of the laboratory tests that along with common clinical features can help to diagnose these defects.
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Coignion C, Banneau G, Goizet C. Paraplegie spastiche ereditarie. Neurologia 2016. [DOI: 10.1016/s1634-7072(16)77572-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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11
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Schüle R, Wiethoff S, Martus P, Karle KN, Otto S, Klebe S, Klimpe S, Gallenmüller C, Kurzwelly D, Henkel D, Rimmele F, Stolze H, Kohl Z, Kassubek J, Klockgether T, Vielhaber S, Kamm C, Klopstock T, Bauer P, Züchner S, Liepelt-Scarfone I, Schöls L. Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients. Ann Neurol 2016; 79:646-58. [DOI: 10.1002/ana.24611] [Citation(s) in RCA: 203] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 02/04/2016] [Accepted: 02/05/2016] [Indexed: 12/14/2022]
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12
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Umetani M. Re-adopting classical nuclear receptors by cholesterol metabolites. J Steroid Biochem Mol Biol 2016; 157:20-6. [PMID: 26563834 PMCID: PMC4724260 DOI: 10.1016/j.jsbmb.2015.11.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 07/10/2015] [Accepted: 11/04/2015] [Indexed: 12/22/2022]
Abstract
Since the first cloning of the human estrogen receptor (ER) α in 1986 and the subsequent cloning of human ERβ, there has been extensive investigation of the role of estrogen/ER. Estrogens/ER play important roles not only in sexual development and reproduction but also in a variety of other functions in multiple tissues. Selective Estrogen Receptor Modulators (SERMs) are ER lignds that act as agonists or antagonists depending on the target genes and tissues, and until recently, only synthetic SERMs have been recognized. However, the discovery of the first endogenous SERM, 27-hydroxycholesterol (27HC), opened a new dimension of ER action in health and disease. In addition to the identification of 27HC as a SERM, oxysterols have been recently demonstrated as indirect modulators of ER through interaction with the nuclear receptor Liver X Receptor (LXR) β. In this review, the recent progress on these novel roles of oxysterols in ER modulation is summarized.
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Affiliation(s)
- Michihisa Umetani
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, 3517 Cullen Blvd, SERC 545, Houston, TX 77204-5056, USA.
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13
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Jahic A, Khundadze M, Jaenisch N, Schüle R, Klimpe S, Klebe S, Frahm C, Kassubek J, Stevanin G, Schöls L, Brice A, Hübner CA, Beetz C. The spectrum of KIAA0196 variants, and characterization of a murine knockout: implications for the mutational mechanism in hereditary spastic paraplegia type SPG8. Orphanet J Rare Dis 2015; 10:147. [PMID: 26572744 PMCID: PMC4647479 DOI: 10.1186/s13023-015-0359-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 10/19/2015] [Indexed: 12/21/2022] Open
Abstract
Background The hereditary spastic paraplegias (HSPs) are rare neurodegenerative gait disorders which are genetically highly heterogeneous. For each single form, eventual consideration of therapeutic strategies requires an understanding of the mechanism by which mutations confer pathogenicity. SPG8 is a dominantly inherited HSP, and associated with rather early onset and rapid progression. A total of nine mutations in KIAA0196, which encodes the WASH regulatory complex (SHRC) member strumpellin, have been reported in SPG8 patients so far. Based on biochemical and cell biological approaches, they have been suggested to act via loss of function-mediated haploinsufficiency. Methods We generated a deletion-based knockout allele for E430025E21Rik, i.e. the murine homologue of KIAA0196. The consequences on mRNA and protein levels were analyzed by qPCR and Western-blotting, respectively. Motor performance was evaluated by the foot-base angle paradigm. Axon outgrowth and relevant organelle compartments were investigated in primary neuron cultures and primary fibroblast cultures, respectively. A homemade multiplex ligation-dependent probe amplification assay enabling identification of large inactivating KIAA0196 deletion alleles was applied to DNA from 240 HSP index patients. Results Homozygous but not heterozygous mice showed early embryonic lethality. No transcripts from the knockout allele were detected, and the previously suggested compensation by the wild-type allele upon heterozygosity was disproven. mRNA expression of genes encoding other SHRC members was unaltered, while there was evidence for reduced SHRC abundance at protein level. We did, however, neither observe HSP-related in vivo and ex vivo phenotypes, nor alterations affecting endosomal, lysosomal, or autophagic compartments. KIAA0196 copy number screening excluded large inactivating deletion mutations in HSP patients. The consequences of monoallelic KIAA0196/E430025E21Rik activation thus differ from those observed for dominant HSP genes for which a loss-of-function mechanism is well established. Conclusions Our data do not support the current view that heterozygous loss of strumpellin/SHRC function leads to haploinsufficiency and, in turn, to HSP. The lethality of homozygous knockout mice, i.e. the effect of complete loss of function, also argues against a dominant negative effect of mutant on wild-type strumpellin in patients. Toxic gain-of-function represents a potential alternative explanation. Confirmation of this therapeutically relevant hypothesis in vivo, however, will require availability of appropriate knockin models. Electronic supplementary material The online version of this article (doi:10.1186/s13023-015-0359-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Amir Jahic
- Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany
| | - Mukhran Khundadze
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Nadine Jaenisch
- Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Rebecca Schüle
- Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.,German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.,Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miami, FL, USA
| | - Sven Klimpe
- Department of Neurology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Stephan Klebe
- Department of Neurology, University Hospital, Freiburg, Germany
| | - Christiane Frahm
- Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Jan Kassubek
- Department of Neurology, University of Ulm, Ulm, Germany
| | - Giovanni Stevanin
- INSERM U1127, Sorbonne Universités, UPMC Univ Paris 06 UMR_S1127, CNRS UMR7225, EPHE, Institut du Cerveau et de la Moelle épinière, Paris, France
| | - Ludger Schöls
- Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.,German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
| | - Alexis Brice
- INSERM U1127, Sorbonne Universités, UPMC Univ Paris 06 UMR_S1127, CNRS UMR7225, EPHE, Institut du Cerveau et de la Moelle épinière, Paris, France
| | | | - Christian Beetz
- Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
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Klebe S, Stevanin G, Depienne C. Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting. Rev Neurol (Paris) 2015; 171:505-30. [PMID: 26008818 DOI: 10.1016/j.neurol.2015.02.017] [Citation(s) in RCA: 125] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 02/10/2015] [Accepted: 02/19/2015] [Indexed: 12/11/2022]
Abstract
Hereditary spastic paraplegias (HSPs) are genetically determined neurodegenerative disorders characterized by progressive weakness and spasticity of lower limbs, and are among the most clinically and genetically heterogeneous human diseases. All modes of inheritance have been described, and the recent technological revolution in molecular genetics has led to the identification of 76 different spastic gait disease-loci with 59 corresponding spastic paraplegia genes. Autosomal recessive HSP are usually associated with diverse additional features (referred to as complicated forms), contrary to autosomal dominant HSP, which are mostly pure. However, the identification of additional mutations and families has considerably enlarged the clinical spectra, and has revealed a huge clinical variability for almost all HSP; complicated forms have also been described for primary pure HSP subtypes, adding further complexity to the genotype-phenotype correlations. In addition, the introduction of next generation sequencing in clinical practice has revealed a genetic and phenotypic overlap with other neurodegenerative disorders (amyotrophic lateral sclerosis, neuropathies, cerebellar ataxias, etc.) and neurodevelopmental disorders, including intellectual disability. This review aims to describe the most recent advances in the field and to provide genotype-phenotype correlations that could help clinical diagnoses of this heterogeneous group of disorders.
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Affiliation(s)
- S Klebe
- Department of neurology, university hospital Würzburg, Josef-Schneider-Straße 11, 97080 Würzburg, Germany
| | - G Stevanin
- Sorbonne universités, UPMC université Paris 06, 91-105, boulevard de l'Hôpital, 75013 Paris, France; ICM, CNRS UMR 7225, Inserm U 1127, 47/83, boulevard de l'Hôpital, 75013 Paris, France; École pratique des hautes études, 4-14, rue Ferrus, 75014 Paris, France; Département de génétique, AP-HP, hôpital Pitié-Salpêtrière, 47/83, boulevard de l'Hôpital, 75013 Paris, France
| | - C Depienne
- Sorbonne universités, UPMC université Paris 06, 91-105, boulevard de l'Hôpital, 75013 Paris, France; ICM, CNRS UMR 7225, Inserm U 1127, 47/83, boulevard de l'Hôpital, 75013 Paris, France; Département de génétique, AP-HP, hôpital Pitié-Salpêtrière, 47/83, boulevard de l'Hôpital, 75013 Paris, France.
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Lee WR, Ishikawa T, Umetani M. The interaction between metabolism, cancer and cardiovascular disease, connected by 27-hydroxycholesterol. ACTA ACUST UNITED AC 2014; 9:617-624. [PMID: 25632306 DOI: 10.2217/clp.14.53] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Oxysterols are metabolites of cholesterol that are produced in liver and other peripheral tissues as a means to eliminate cholesterol to bile acid. Recent studies have revealed that the most abundant circulating oxysterol 27-hydroxycholesterol (27HC) is the first identified endogenous selective estrogen receptor modulator. 27HC levels correlate well with that of cholesterol, and also rise progressively with age. 27HC affects estrogen receptor function by the antagonism of estrogen action and also by the direct modulation of the receptor function, and similar to estrogen/estrogen receptors, 27HC has many actions in various tissues. This review article introduces the recent progress in the understanding of the role of 27HC in breast cancer and cardiovascular dysfunction.
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Affiliation(s)
- Wan-Ru Lee
- Division of Pulmonary & Vascular Biology, Departments of Pediatrics & Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
| | - Tomonori Ishikawa
- Division of Pulmonary & Vascular Biology, Departments of Pediatrics & Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA ; Comprehensive Reproductive Medicine, Graduate School of Medical & Dental Sciences, Tokyo Medical & Dental University, Tokyo, Japan
| | - Michihisa Umetani
- Division of Pulmonary & Vascular Biology, Departments of Pediatrics & Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
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Lo Giudice T, Lombardi F, Santorelli FM, Kawarai T, Orlacchio A. Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms. Exp Neurol 2014; 261:518-39. [PMID: 24954637 DOI: 10.1016/j.expneurol.2014.06.011] [Citation(s) in RCA: 254] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Revised: 06/07/2014] [Accepted: 06/12/2014] [Indexed: 12/12/2022]
Abstract
Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurological disorders characterized by pathophysiologic hallmark of length-dependent distal axonal degeneration of the corticospinal tracts. The prominent features of this pathological condition are progressive spasticity and weakness of the lower limbs. To date, 72 spastic gait disease-loci and 55 spastic paraplegia genes (SPGs) have been identified. All modes of inheritance (autosomal dominant, autosomal recessive, and X-linked) have been described. Recently, a late onset spastic gait disorder with maternal trait of inheritance has been reported, as well as mutations in genes not yet classified as spastic gait disease. Several cellular processes are involved in its pathogenesis, such as membrane and axonal transport, endoplasmic reticulum membrane modeling and shaping, mitochondrial function, DNA repair, autophagy, and abnormalities in lipid metabolism and myelination processes. Moreover, recent evidences have been found about the impairment of endosome membrane trafficking in vesicle formation and about the involvement of oxidative stress and mtDNA polymorphisms in the onset of the disease. Interactome networks have been postulated by bioinformatics and biological analyses of spastic paraplegia genes, which would contribute to the development of new therapeutic approaches.
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Affiliation(s)
- Temistocle Lo Giudice
- Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC) - Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Rome, Italy; Dipartimento di Medicina dei Sistemi, Università di Roma "Tor Vergata", Rome, Italy
| | - Federica Lombardi
- Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC) - Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Rome, Italy
| | - Filippo Maria Santorelli
- Unità Operativa Complessa di Medicina Molecolare, Neurogenetica e Malattie Neurodegenerative, IRCCS Stella Maris, Pisa, Italy
| | - Toshitaka Kawarai
- Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, Tokushima, Japan
| | - Antonio Orlacchio
- Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC) - Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Rome, Italy; Dipartimento di Medicina dei Sistemi, Università di Roma "Tor Vergata", Rome, Italy.
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Central motor conduction studies in patients with spinal cord disorders: a review. Spinal Cord 2014; 52:420-7. [DOI: 10.1038/sc.2014.48] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Revised: 03/17/2014] [Accepted: 03/22/2014] [Indexed: 11/09/2022]
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Lan MY, Yeh TH, Chang YY, Kuo HC, Sun HS, Lai SC, Lu CS. Clinical and genetic analysis of Taiwanese patients with hereditary spastic paraplegia type 5. Eur J Neurol 2014; 22:211-4. [PMID: 24641183 DOI: 10.1111/ene.12407] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 02/07/2014] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND PURPOSE Spastic paraplegia type 5 (SPG5) is an autosomal recessive (AR) hereditary spastic paraplegia (HSP) associated with pure or complicated phenotypes. This study aimed to screen SPG5 in Taiwanese HSP patients. METHODS Sequencing of the SPG5 gene, CYP7B1, was performed in a cohort of 25 ethnic Han Taiwanese patients with AR or sporadic HSP. Clinical information and magnetic resonance imaging (MRI) were analyzed in confirmed SPG5 patients. RESULTS One (33%) AR kindred and four (18%) sporadic cases had CYP7B1 mutations. All of the SPG5 cases carried the mutation c.334 C>T (R112X). Haplotype analysis suggested a 'founder effect' in ethnic Hans for this mutation. The phenotype was either pure or complicated by cerebellar ataxia. For the primary HSP phenotype, there were profound dorsal column sensory deficits in all patients. Spine MRI showed thoraco-lumbar cord atrophy in some patients. CONCLUSIONS Spastic paraplegia type 5 is a common cause of AR and sporadic HSPs that has a higher frequency in Taiwanese than in other ethnic groups. It is associated with a CYP7B1 founder mutation and its phenotype is characterized by pronounced dorsal column sensory loss, with cerebellar ataxia in some patients.
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Affiliation(s)
- M-Y Lan
- Center for Parkinson's Disease, Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Yantsevich AV, Dichenko YV, Mackenzie F, Mukha DV, Baranovsky AV, Gilep AA, Usanov SA, Strushkevich NV. Human steroid and oxysterol 7α-hydroxylase CYP7B1: substrate specificity, azole binding and misfolding of clinically relevant mutants. FEBS J 2014; 281:1700-13. [PMID: 24491228 DOI: 10.1111/febs.12733] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 12/23/2013] [Accepted: 01/28/2014] [Indexed: 11/28/2022]
Abstract
Oxysterols and neurosteroids are important signaling molecules produced by monooxygenases of the cytochrome P450 family that realize their effect through nuclear receptors. CYP7B1 catalyzes the 6- or 7-hydroxylation of both steroids and oxysterols and thus is involved in the metabolism of neurosteroids and bile acid synthesis, respectively. The dual physiological role of CYP7B1 is evidenced from different diseases, liver failure and progressive neuropathy, caused by enzyme malfunction. Here we present biochemical characterization of CYP7B1 at the molecular level to understand substrate specificity and susceptibility to azole drugs. Based on our experiments with purified enzyme, the requirements for CYP7B1 hydroxylation of steroid molecules are as follows: C5 hydrogen in the α-configuration (or double bond at C5), a polar group at C17, a hydroxyl group at C3, and the absence of the hydroxyl group at C20-C24 in the C27-sterol side chain. 21-hydroxy-pregnenolone was identified as a new substrate, and overall low activity toward pregnanes could be related to the increased potency of 7-hydroxy derivatives produced by CYP7B1. Metabolic conversion (deactivation) of oxysterols by CYP7B1 in a reconstituted system proceeds via two sequential hydroxylations. Two mutations that are found in patients with diseases, Gly57Arg and Phe216Ser, result in apo-P450 (devoid of heme) protein formation. Our CYP7B1 homology model provides a rationale for understanding clinical mutations and relatively broad substrate specificity for steroid hydroxylase.
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Leoni V, Caccia C. Potential diagnostic applications of side chain oxysterols analysis in plasma and cerebrospinal fluid. Biochem Pharmacol 2013; 86:26-36. [DOI: 10.1016/j.bcp.2013.03.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Revised: 03/18/2013] [Accepted: 03/20/2013] [Indexed: 12/20/2022]
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Abstract
The cytochrome P450 superfamily consists of a large number of heme-containing monooxygenases. Many human P450s metabolize drugs used to treat human diseases. Others are necessary for synthesis of endogenous compounds essential for human physiology. In some instances, alterations in specific P450s affect the biological processes that they mediate and lead to a disease. In this minireview, we describe medically significant human P450s (from families 2, 4, 7, 11, 17, 19, 21, 24, 27, 46, and 51) and the diseases associated with these P450s.
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Affiliation(s)
- Irina A Pikuleva
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
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Denora PS, Santorelli FM, Bertini E. Hereditary spastic paraplegias: one disease for many genes, and still counting. HANDBOOK OF CLINICAL NEUROLOGY 2013; 113:1899-912. [PMID: 23622413 DOI: 10.1016/b978-0-444-59565-2.00060-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Hereditary spastic paraplegias (HSPs) are genetically heterogeneous Mendelian disorders characterized by spastic gait with stiffness and weakness in the legs and an associated plethora of neurological or extraneurological signs in "complicated" forms. Major advances have been made during the past two decades in our understanding of their molecular bases with the identification of a large number of gene loci and the cloning of a set of them. The combined genetic and clinical information obtained has permitted a new, molecularly-driven classification and an improved diagnosis of these conditions. This represents a prerequisite for better counseling in families and more appropriate therapeutic options. However, further heterogeneity is expected and new insight into the possible mechanisms anticipated.
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Affiliation(s)
- Paola S Denora
- Molecular Medicine and Unit of Neuromuscular and Neurodegenerative Diseases, IRCCS-Children's Hospital Bambino Gesù, Rome, Italy
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Leoni V, Caccia C. Relationship between cholesterol metabolism, ApoE and brain volumes in Alzheimer’s disease. FUTURE NEUROLOGY 2011. [DOI: 10.2217/fnl.11.38] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
APOE genotype, aging and midlife hypercholesterolemia are well-established risk factors for late-onset Alzheimer’s disease (AD). ApoE and cholesterol are involved in the pathogenesis of AD since they influence amyloid-β accumulation and Tau pathology. APOE ε4 carriers were found to present lower levels of amyloid-β1–42, higher tau and phosphorylated tau and a higher degree of brain atrophy at any disease stage. Presence of ApoE4 shifts the onset of the disease towards a younger age and makes progression faster. Hypercholesterolemia together with other major cardiovascular risk factors were found to be involved in the pathogenesis of AD, but reduced plasma cholesterol levels were described in demented patients. Significant correlations were found between cholesterol precursors lathosterol, lanosterol and 24S-hydroxycholesterol (a putative marker of brain cholesterol turnover) in plasma and brain atrophy as quantified by MRI. It is likely that neurodegeneration affects both brain and whole-body cholesterol metabolism in AD.
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Affiliation(s)
- Valerio Leoni
- Laboratory of Clinical Pathology & Medical Genetics, R17, IRCCS National Institute of Neurology ‘C Besta’, Via Celoria 11, 20133 Milano, Italy
| | - Claudio Caccia
- Laboratory of Clinical Pathology & Medical Genetics, R17, IRCCS National Institute of Neurology ‘C Besta’, Via Celoria 11, 20133 Milano, Italy
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Leoni V, Caccia C. Oxysterols as biomarkers in neurodegenerative diseases. Chem Phys Lipids 2011; 164:515-24. [DOI: 10.1016/j.chemphyslip.2011.04.002] [Citation(s) in RCA: 139] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2011] [Revised: 04/06/2011] [Accepted: 04/08/2011] [Indexed: 10/18/2022]
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Mateos L, Ismail MAM, Gil-Bea FJ, Schüle R, Schöls L, Heverin M, Folkesson R, Björkhem I, Cedazo-Mínguez A. Side chain-oxidized oxysterols regulate the brain renin-angiotensin system through a liver X receptor-dependent mechanism. J Biol Chem 2011; 286:25574-85. [PMID: 21628469 PMCID: PMC3138324 DOI: 10.1074/jbc.m111.236877] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Revised: 05/26/2011] [Indexed: 12/26/2022] Open
Abstract
Disturbances in cholesterol metabolism have been associated with hypertension and neurodegenerative disorders. Because cholesterol metabolism in the brain is efficiently separated from plasma cholesterol by the blood-brain barrier (BBB), it is an unsolved paradox how high blood cholesterol can cause an effect in the brain. Here, we discuss the possibility that cholesterol metabolites permeable to the BBB might account for these effects. We show that 27-hydroxycholesterol (27-OH) and 24S-hydroxycholesterol (24S-OH) up-regulate the renin-angiotensin system (RAS) in the brain. Brains of mice on a cholesterol-enriched diet showed up-regulated angiotensin converting enzyme (ACE), angiotensinogen (AGT), and increased JAK/STAT activity. These effects were confirmed in in vitro studies with primary neurons and astrocytes exposed to 27-OH or 24S-OH, and were partially mediated by liver X receptors. In contrast, brain RAS activity was decreased in Cyp27a1-deficient mice, a model exhibiting reduced 27-OH production from cholesterol. Moreover, in humans, normocholesterolemic patients with elevated 27-OH levels, due to a CYP7B1 mutation, had markers of activated RAS in their cerebrospinal fluid. Our results demonstrate that side chain-oxidized oxysterols are modulators of brain RAS. Considering that levels of cholesterol and 27-OH correlate in the circulation and 27-OH can pass the BBB into the brain, we suggest that this cholesterol metabolite could be a link between high plasma cholesterol levels, hypertension, and neurodegeneration.
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Affiliation(s)
- Laura Mateos
- From the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, NOVUM, SE-14186 Stockholm, Sweden
| | - Muhammad-Al-Mustafa Ismail
- From the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, NOVUM, SE-14186 Stockholm, Sweden
| | - Francisco-Javier Gil-Bea
- From the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, NOVUM, SE-14186 Stockholm, Sweden
| | - Rebecca Schüle
- the Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tubingen, 72076 Tubingen, Germany, and
| | - Ludger Schöls
- the Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tubingen, 72076 Tubingen, Germany, and
| | - Maura Heverin
- the Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska University Hospital, 14186 Huddinge, Sweden
| | - Ronnie Folkesson
- From the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, NOVUM, SE-14186 Stockholm, Sweden
| | - Ingemar Björkhem
- the Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska University Hospital, 14186 Huddinge, Sweden
| | - Angel Cedazo-Mínguez
- From the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, NOVUM, SE-14186 Stockholm, Sweden
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Schlipf NA, Schüle R, Klimpe S, Karle KN, Synofzik M, Schicks J, Riess O, Schöls L, Bauer P. Amplicon-based high-throughput pooled sequencing identifies mutations in CYP7B1 and SPG7 in sporadic spastic paraplegia patients. Clin Genet 2011; 80:148-60. [DOI: 10.1111/j.1399-0004.2011.01715.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Clayton PT. Disorders of bile acid synthesis. J Inherit Metab Dis 2011; 34:593-604. [PMID: 21229319 DOI: 10.1007/s10545-010-9259-3] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Revised: 11/30/2010] [Accepted: 12/01/2010] [Indexed: 12/14/2022]
Abstract
Inborn errors of bile acid synthesis can produce life-threatening cholestatic liver disease (which usually presents in infancy) and progressive neurological disease presenting later in childhood or in adult life. Both types of disease can often be treated very effectively with bile acid replacement therapy and it is therefore important to diagnose these disorders as early as possible. The cholestatic disease in infancy is characterised by conjugated hyperbilirubinaemia with raised transaminases but normal γ-glutamyl transpeptidase and a biopsy showing a giant cell hepatitis. There is usually evidence of fat-soluble vitamin malabsorption. The neurological presentation often includes signs of upper motor neurone damage (spastic paraparesis). The most useful screening test for many of these disorders is analysis of urinary cholanoids (bile acids and bile alcohols); this is usually now achieved by electrospray ionisation tandem mass spectrometry. The disorders that are discussed in this review are: 3β-hydroxysteroid-Δ5-C27-steroid dehydrogenase deficiency, Δ4-3-oxosteroid 5β-reductase deficiency, sterol 27-hydroxylase deficiency (cerberotendinous xanthomatosis, CTX), oxysterol 7α-hydroxylase deficiency (including one form of hereditary spastic paraparesis) and the amidation defects, bile acid-CoA: aminoacid N-acyltransferase (BAAT) deficiency and bile acid-CoA ligase deficiency. The disorders of peroxisome biogenesis and peroxisomal β-oxidation that affect bile acid synthesis will be covered in the review by Ferdinandusse et al.
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Affiliation(s)
- Peter Theodore Clayton
- Biochemistry Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health (and Great Ormond Street Hospital for Children), 30 Guilford Street, London WC1N 1EH, UK.
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Cao L, Fei QZ, Tang WG, Liu JR, Zheng L, Xiao Q, He SB, Fu Y, Chen SD. Novel mutations in theCYP7B1gene cause hereditary spastic paraplegia. Mov Disord 2011; 26:1354-6. [DOI: 10.1002/mds.23466] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2010] [Revised: 08/09/2010] [Accepted: 09/10/2010] [Indexed: 11/08/2022] Open
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Fex Svenningsen A, Wicher G, Lundqvist J, Pettersson H, Corell M, Norlin M. Effects on DHEA levels by estrogen in rat astrocytes and CNS co-cultures via the regulation of CYP7B1-mediated metabolism. Neurochem Int 2011; 58:620-4. [PMID: 21300119 DOI: 10.1016/j.neuint.2011.01.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2010] [Revised: 12/17/2010] [Accepted: 01/20/2011] [Indexed: 11/29/2022]
Abstract
The neurosteroid dehydroepiandrosterone (DHEA) is formed locally in the CNS and has been implicated in several processes essential for CNS function, including control of neuronal survival. An important metabolic pathway for DHEA in the CNS involves the steroid hydroxylase CYP7B1. In previous studies, CYP7B1 was identified as a target for estrogen regulation in cells of kidney and liver. In the current study, we examined effects of estrogens on CYP7B1-mediated metabolism of DHEA in primary cultures of rat astrocytes and co-cultures of rat CNS cells. Astrocytes, which interact with neurons in several ways, are important for brain neurosteroidogenesis. We found that estradiol significantly suppressed CYP7B1-mediated DHEA hydroxylation in primary mixed CNS cultures from fetal and newborn rats. Also, CYP7B1-mediated DHEA hydroxylation and CYP7B1 mRNA were markedly suppressed by estrogen in primary cultures of rat astrocytes. Interestingly, diarylpropionitrile, a well-known agonist of estrogen receptor β, also suppressed CYP7B1-mediated hydroxylation of DHEA. Several previous studies have reported neuroprotective effects of estrogens. The current data indicate that one of the mechanisms whereby estrogen can exert protective effects in the CNS may involve increase of the levels of DHEA by suppression of its metabolism.
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Arnoldi A, Crimella C, Tenderini E, Martinuzzi A, D'Angelo MG, Musumeci O, Toscano A, Scarlato M, Fantin M, Bresolin N, Bassi MT. Clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations. Clin Genet 2011; 81:150-7. [PMID: 21214876 DOI: 10.1111/j.1399-0004.2011.01624.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Spastic paraplegia type 5 (SPG5) is caused by mutations in CYP7B1, a gene encoding the cytochrome P-450 oxysterol 7-α-hydroxylase, CYP7B1, an enzyme implicated in the cholesterol metabolism. Mutations in CYP7B1 were found in both pure and complicated forms of the disease with a mutation frequency of 7.7% in pure recessive cases. The mutation frequency in complex forms, approximately 6.6%, is more controversial and needs to be refined. We studied in more detail the SPG5-related spectrum of complex phenotypes by screening CYPB1 for mutations in a large cohort of 105 Italian hereditary spastic paraplegias (HSPs) index patients including 50 patients with a complicated HSP (cHSP) phenotype overlapping the SPG11- and the SPG15-related forms except for the lack of thin corpus callosum and 55 pure patients. Five CYP7B1 mutations, three of which are novel, were identified in four patients, two with a complex form of the disease and two with a pure phenotype. The CYP7B1 mutation frequencies obtained in both complicated and pure familial cases are comparable to the known ones. These results obtained extend the range of SPG5-related phenotypes and reveal variability in clinical presentation, disease course and functional profile in the SPG5-related patients while providing with some clues for molecular diagnosis in cHSP.
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Affiliation(s)
- A Arnoldi
- E. Medea Scientific Institute, Laboratory of Molecular Biology, Bosisio Parini, Lecco, Italy
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Manganelli F, Pisciotta C, Dubbioso R, Iodice R, Criscuolo C, Ruggiero L, De Michele G, Santoro L. Electrophysiological characterisation in hereditary spastic paraplegia type 5. Clin Neurophysiol 2010; 122:819-22. [PMID: 21111673 DOI: 10.1016/j.clinph.2010.10.025] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Revised: 10/12/2010] [Accepted: 10/14/2010] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To assess in SPG5 hereditary spastic paraparesis (HSP) the involvement of the central (CNS) and the peripheral (PNS) nervous system by a multimodal electrophysiological approach. METHODS Four patients belonging to three HSP families, with a molecular diagnosis of SPG5, underwent electrophysiological evaluation including electromyography (EMG) and nerve conduction study (NCS), motor-evoked potentials (MEPs) by transcranial magnetic stimulation (TMS) and somatosensory evoked potentials (SEPs) at upper and lower limbs, visual (VEPs) and brainstem auditory evoked potentials (BAEPs). In one patient, electrophysiological evaluation was performed twice at the age of 12 and 31 years. RESULTS EMG and NCS were normal. MEPs and SEPs were abnormal in all patients along the central pathway for upper and/or lower limbs. VEPs revealed a damage of visual pathway and BAEPs showed the involvement of auditory pathway within the brainstem. In the patient who underwent electrophysiological follow-up, MEP and SEP findings were unmodified, whereas VEPs showed no reproducible responses. CONCLUSIONS We report an extensive electrophysiological evaluation of SPG5 and we confirm that the SPG5 phenotype may be broader than pure presentation. SIGNIFICANCE Electrophysiological evaluation, showing diffuse CNS involvement with PNS sparing, could be very useful to address the molecular diagnosis and to follow-up a hypothetical treatment.
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Affiliation(s)
- Fiore Manganelli
- Department of Neurological Sciences, University Federico II of Naples, Naples, Italy
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Björkhem I, Leoni V, Meaney S. Genetic connections between neurological disorders and cholesterol metabolism. J Lipid Res 2010; 51:2489-503. [PMID: 20466796 PMCID: PMC2918434 DOI: 10.1194/jlr.r006338] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2010] [Revised: 05/13/2010] [Indexed: 12/25/2022] Open
Abstract
Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defined defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington's disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally associated with disturbances in cholesterol metabolism, and presence of the E4 isoform of the cholesterol transporter apolipoprotein E as well as hypercholesterolemia are important risk factors for development of Alzheimer's disease. In the present review, we discuss the links between genetic disturbances in cholesterol metabolism and the above neurological disorders.
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Affiliation(s)
- Ingemar Björkhem
- Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
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A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42). Eur J Hum Genet 2010; 18:1065-7. [PMID: 20461110 DOI: 10.1038/ejhg.2010.68] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The most frequent causes of autosomal dominant (AD) hereditary spastic paraplegias (HSP) (ADHSP) are mutations in the SPAST gene (SPG4 locus). However, roughly 60% of patients are negative for SPAST mutations, despite their family history being compatible with AD inheritance. A mutation in the gene for an acetyl-CoA transporter (SLC33A1) has recently been reported in one Chinese family to cause ADHSP-type SPG42. In this study, we screened 220 independent SPAST mutation-negative ADHSP samples for mutations in the SLC33A1 gene by high-resolution melting curve analysis. Conspicuous samples were validated by direct sequencing. Moreover, copy number variations affecting SLC33A1 were screened by multiplex ligation-dependent probe amplification assay. We could not identify potentially disease-causing mutations in our patients either by mutation scanning or by gene dosage analysis, as for the latter specific positive controls are not available to date. As our sample represents ADHSP patients for whom SPAST mutations and almost in all cases ATL1 and REEP1 mutations had been excluded, we consider SLC33A1 gene mutations as being very rare in a European ADHSP cohort, if present at all. To date, as SPG42 has still not been identified in a second, unrelated family, systematic genetic testing for SLC33A1 mutations is not recommended.
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Stiles AR, McDonald JG, Bauman DR, Russell DW. CYP7B1: one cytochrome P450, two human genetic diseases, and multiple physiological functions. J Biol Chem 2009; 284:28485-9. [PMID: 19687010 PMCID: PMC2781391 DOI: 10.1074/jbc.r109.042168] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The CYP7B1 cytochrome P450 enzyme hydroxylates carbons 6 and 7 of the B ring of oxysterols and steroids. Hydroxylation reduces the biological activity of these substrates and facilitates their conversion to end products that are readily excreted from the body. CYP7B1 is expressed in the liver, reproductive tract, and brain and performs different physiological functions in each tissue. Hepatic CYP7B1 activity is crucial for the inactivation of oxysterols and their subsequent conversion into bile salts. Loss of CYP7B1 activity is associated with liver failure in children. In the reproductive tract, the enzyme metabolizes androgens that antagonize estrogen action; mice without CYP7B1 have abnormal prostates and ovaries. The role of CYP7B1 in brain is under investigation; recent studies show that spastic paraplegia type 5, a progressive neuropathy, is caused by loss-of-function mutations in the human gene.
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Affiliation(s)
- Ashlee R. Stiles
- From the Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046
| | - Jeffrey G. McDonald
- From the Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046
| | - David R. Bauman
- From the Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046
| | - David W. Russell
- From the Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046
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Schüle R, Siddique T, Deng HX, Yang Y, Donkervoort S, Hansson M, Madrid RE, Siddique N, Schöls L, Björkhem I. Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis. J Lipid Res 2009; 51:819-23. [PMID: 19812052 DOI: 10.1194/jlr.m002543] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Patients with a recessively inherited "pure" hereditary spastic paresis (SPG5) have mutations in the gene coding for the oxysterol 7 alpha hydroxylase (CYP7B1). One of the expected metabolic consequences of such mutations is accumulation of oxysterol substrates due to decreased enzyme activity. In accordance with this, we demonstrate here that four patients with the SPG5 disease have 6- to 9-fold increased plasma levels of 27-hydroxycholesterol. A much higher increase, 30- to 50-fold, was found in cerebrospinal fluid. The plasma levels of 25-hydroxycholesterol were increased about 100-fold. There were no measurable levels of this oxysterol in cerebrospinal fluid. The pattern of bile acids in serum was normal, suggesting a normal bile acid synthesis. The findings are discussed in relation to two transgenic mouse models with increased levels of 27-hydroxy cholesterol in the circulation but without neurological symptoms: the cyp27a1 transgenic mouse and the cyp7b1 knockout mouse. The absolute plasma levels of 27-hydroxycholesterol in the latter models are, however, only about 20% of those in the SPG5 patients. If the accumulation of 27-hydroxycholesterol is an important pathogenetic factor, a reduction of its levels may reduce or prevent the neurological symptoms. A possible strategy to achieve this is discussed.
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Affiliation(s)
- Rebecca Schüle
- Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tubingen, Tubingen, Germany
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