Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies
| العنوان: | Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies |
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| المؤلفون: | R. Hermann, Tobias Willer, Ute Hehr, G. Uyanik, Sabine Strahl, J.H.L.M. van Bokhoven, C. Korner, Thomas Voit, Ivo Barić, Mark Lommel, Sebahattin Cirak |
| المصدر: | Neurology, 74, 2, pp. 157-64 Neurology, 74, 157-64 |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Genetic Markers, Male, Genotype, Genetics and epigenetic pathways of disease [NCMLS 6], DNA Mutational Analysis, Mutant, Medizin, Down-Regulation, Biology, Compound heterozygosity, Mannosyltransferases, Gene Expression Regulation, Enzymologic, Abnormal glycosylation, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, Genetic Predisposition to Disease, Genetic Testing, Child, Dystroglycans, dystroglycanopathies, protein O-mannosyltransferases, dermal fibroblasts, Cells, Cultured, 030304 developmental biology, Genetics, 0303 health sciences, Splice site mutation, fungi, Fibroblasts, medicine.disease, Molecular biology, Phenotype, 3. Good health, Muscular Dystrophies, Limb-Girdle, Mutation, Mannosyltransferase activity, RNA Splice Sites, Rabbits, Neurology (clinical), Functional Neurogenomics [DCN 2], 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy |
| الوصف: | Contains fulltext : 87607.pdf (Publisher’s version ) (Open Access) BACKGROUND: Mutations in protein O-mannosyltransferases (POMTs) cause a heterogeneous group of muscular dystrophies with abnormal glycosylation of alpha-dystroglycan (dystroglycanopathies). The wide spectrum of clinical severities ranges from Walker-Warburg syndrome (WWS), associated with brain and eye abnormalities, to mild forms of limb girdle muscular dystrophy (LGMD). OBJECTIVE: The aim of this study was to elucidate the impact of mutations in POMT1 on the clinical phenotype. METHODS: We examined 2 patients with POMT1-associated alpha-dystroglycanopathy, 1 displaying a LGMD2K and 1 with a WWS phenotype. Using dermal fibroblasts, we analyzed the influence of the POMT1 mutations on the glycosylation status of alpha-dystroglycan, protein O-mannosyltransferase activity, and the stability of the mutant POMT1 protein. RESULTS: We report on novel compound heterozygous mutations in POMT1 (p.L171A and p.A589VfsX38) that result in LGMD2K. We further demonstrate that a homozygous splice site mutation of a recently identified WWS patient results in POMT1 p.del77-93. Using dermal fibroblasts, we show that mannosyltransferase activity is reduced in the patients and that stability of POMT1 mutant proteins p.A589VfsX38 and p.del77-93 is significantly decreased. CONCLUSIONS: Our results suggest that dermal fibroblasts can be applied to facilitate the diagnostic analysis of dystroglycanopathy patients as well as to study the pathogenic mechanism of POMT mutations. Characterization of the POMT1 substrate protein alpha-dystroglycan and POMT in vitro mannosyltransferase activity shows that the severity of the clinical phenotype of the patients analyzed is inversely correlated with POMT activity. |
| وصف الملف: | application/pdf |
| تدمد: | 0028-3878 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2da0c3d9f05a2dd9e67f7ca0304bf5a7 https://hdl.handle.net/2066/87607 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2da0c3d9f05a2dd9e67f7ca0304bf5a7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00283878 |
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