Early Onset Collagen VI Myopathies: Genetic and Clinical Correlations
| Autor: | Louis Viollet, C. Gartioux, Valérie Allamand, Carmen Navarro, Murielle Dunand, E. Lacène, Filip Roelens, Denys Chaigne, Norma B. Romero, Kim Maincent, Soledad Monges, Isabelle Pénisson-Besnier, Thierry Kuntzer, Laura Briñas, Isabelle Desguerre, Tanya Stojkovic, Goknur Haliloglu, Pierre-Yves Jeannet, C. Ledeuil, Christine E. M. de Die-Smulders, Christine Tranchant, Susana Quijano-Roy, Ana Lia Taratuto, Annick Toutain, Bernard Echenne, Haluk Topaloglu, Pascale Guicheney, Brigitte Estournet, Luciano Merlini, Svetlana Maugenre, François Rivier, Fabiana Lubieniecki, Michèle Mayer, S. Makri, Pascale Richard, Ghislaine Plessis, Ana Ferreiro, Bruno Eymard |
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| Přispěvatelé: | Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Çocuk Sağlığı ve Hastalıkları |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Collagen Type VII Adolescent Ullrich congenital muscular dystrophy Statistics as Topic Glycine Biology medicine.disease_cause Young Adult Muscular Diseases Collagen VI medicine Missense mutation Humans Genetic Testing Myopathy Child Muscle Skeletal Gene Cells Cultured Genetics Mutation Bethlem myopathy Fibroblasts medicine.disease Exon skipping congenital muscular-dystrophy messenger-rna decay bethlem myopathy vonwillebrand-factor sequence-analysis globular domains ullrich-disease col6a1 gene mutations severity Europe Phenotype Neurology Child Preschool Female Neurology (clinical) Neurosciences & Neurology medicine.symptom |
| Zdroj: | Annals of Neurology, 68(4), 511-520. Wiley Annals of Neurology, vol. 68, no. 4, pp. 511-520 |
| ISSN: | 0364-5134 |
| Popis: | Objective Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations. Methods Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%). ColVI secretion was analyzed in patient-derived skin fibroblasts. Chain-specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification was performed by sequencing of complementary DNA. Results ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in-frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC-causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in-frame exon skipping and glycine missense mutations were identified in patients of the moderate-progressive group (loss of ambulation). Interpretation This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time-consuming, and demonstrates that quantitative RT-PCR is a helpful tool for the identification of some mutation-bearing genes. Moreover, the clinical classification proposed allowed genotype-phenotype relationships to be explored, and may be useful in the design of future clinical trials. ANN NEUROL 2010;68:511–520 |
| Databáze: | OpenAIRE |
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