Clinical, Pathologic, and Genetic Features of Collagen VI-Related Myopathy in Korea
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Background and Purpose Mutations in collagen VI-related genes (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). These were previously believed to be separate disease entities, but they are now both classified as collagen VI-related myopathies, which cover a broad clinical spectrum. We aimed to analyze the clinical, pathologic, and genetic characteristics of patients with collagen VI-related myopathy in Korea. Methods We reviewed the clinical, pathologic, and genetic features in 22 patients with collagen VI-related myopathy from 13 families, as confirmed by genetic analysis of collagen VI-related genes. Results The mean ages of the 22 patients at first symptom presentation and diagnosis were 4.5 and 24.9 years, respectively. Four patients in 4 families showed the phenotype of intermediate collagen VI-related myopathies (IM), 16 patients in 7 families had the BM phenotype, and 2 patients in 2 families presented with the typical UCMD phenotype. Based on genetic analysis, five patients (five families) comprising four with IM and one with typical UCMD had missense mutations in the triple-helical domain of COL6A1, and ten patients (four families) with BM showed exon-14-skipping mutations. Additionally, we found two novel mutations: c.956A> G (p.K319R) in COL6A1 and c.6221G>T (p.G2074V) in COL6A3. Conclusions Missense mutations in the triple-helical domain of COL6A1 are the most common mutations related to collagen VI-related myopathy in Korea. Patients with these mutations have a tendency toward an earlier disease onset and more severe progression compared to patients with other mutations.
Abstract
Background and Purpose Mutations in collagen VI-related genes (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). These were previously believed to be separate disease entities, but they are now both classified as collagen VI-related myopathies, which cover a broad clinical spectrum. We aimed to analyze the clinical, pathologic, and genetic characteristics of patients with collagen VI-related myopathy in Korea. Methods We reviewed the clinical, pathologic, and genetic features in 22 patients with collagen VI-related myopathy from 13 families, as confirmed by genetic analysis of collagen VI-related genes. Results The mean ages of the 22 patients at first symptom presentation and diagnosis were 4.5 and 24.9 years, respectively. Four patients in 4 families showed the phenotype of intermediate collagen VI-related myopathies (IM), 16 patients in 7 families had the BM phenotype, and 2 patients in 2 families presented with the typical UCMD phenotype. Based on genetic analysis, five patients (five families) comprising four with IM and one with typical UCMD had missense mutations in the triple-helical domain of COL6A1, and ten patients (four families) with BM showed exon-14-skipping mutations. Additionally, we found two novel mutations: c.956A> G (p.K319R) in COL6A1 and c.6221G>T (p.G2074V) in COL6A3. Conclusions Missense mutations in the triple-helical domain of COL6A1 are the most common mutations related to collagen VI-related myopathy in Korea. Patients with these mutations have a tendency toward an earlier disease onset and more severe progression compared to patients with other mutations.
참고문헌 (23)
- Lampe AK, "Collagen VI related muscle disorders", J Med Genet, 42, pp.673~685 (2005)
- Bönnemann CG, "The collagen VI-related myopathies: muscle meets its matrix", Nat Rev Neurol, 7, pp.379~390 (2011)
- Foley AR, "Natural history of pulmonary function in collagen VI-related myopathies", Brain, 136, pp.3625~3633 (2013)
- Briñas L, "Early onset collagen VI myopathies: genetic and clinical correlations", Ann Neurol, 68, pp.511~520 (2010)
- Bethlem J, "Benign myopathy, with autosomal dominant inheritance. A report on three pedigrees", Brain, 99, pp.91~100 (1976)
- 서범천, "베들렘 근병증 1가계", 대한신경과학회지, 24(6), pp.614~617 (2006), 대한신경과학회
- Yoonhong Park, "Ullrich Congenital Muscular Dystrophy Possibly Related With COL6A1 p.Gly302Arg Variant", Annals of Rehabilitation Medicine, 38(2), pp.292~296 (2014), 대한재활의학회
- 박영은, "COL6A1 돌연변이에 의해 발생한 산발성 Ullrich 병 1례", Annals of Clinical Neurophysiology, 12(1), pp.27~31 (2010), 대한임상신경생리학회
- Chae JH, "Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders", J Med Genet, 52, pp.208~216 (2015)
- 박형준, "Molecular Genetic Diagnosis of a Bethlem Myopathy Family with an Autosomal-Dominant COL6A1 Mutation, as Evidenced by Exome Sequencing", Journal of Clinical Neurology, 11(2), pp.183~187 (2015), 대한신경과학회[DOI]
- Park HJ, "Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders", Clin Genet, 91, pp.403~410 (2017)
- Fu J, "'Target' and 'Sandwich' signs in thigh muscles have high diagnostic values for collagen VI-related myopathies", Chin Med J (Engl), 129, pp.1811~1816 (2016)
- Okada M, "Primary collagen VI deficiency is the second most common congenital muscular dystrophy in Japan", Neurology, 69, pp.1035~1042 (2007)
- Pace RA, "Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity", Ann Neurol, 64, pp.294~303 (2008)
- Richards S, "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology", Genet Med, 17, pp.405~424 (2015)
- Lampe AK, "Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy", J Med Genet, 42, pp.108~120 (2005)
- Lucioli S, "Detection of common and private mutations in the COL6A1 gene of patients with Bethlem myopathy", Neurology, 64, pp.1931~1937 (2005)
- Vanegas OC, "Novel COL6A1 splicing mutation in a family affected by mild Bethlem myopathy", Muscle Nerve, 25, pp.513~519 (2002)
- Yonekawa T, "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)", J Neurol Neurosurg Psychiatry, 86, pp.280~287 (2015)
- Giusti B, "Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy", Ann Neurol, 58, pp.400~410 (2005)
- Pan TC, "New molecular mechanism for Ullrich congenital muscular dystrophy:a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype", Am J Hum Genet, 73, pp.355~369 (2003)
- Baker NL, "Molecular consequences of dominant Bethlem myopathy collagen VI mutations", Ann Neurol, 62, pp.390~405 (2007)
- Pepe G, "A heterozygous splice site mutation in COL6A1 leading to an in-frame deletion of the alpha1(VI) collagen chain in an italian family affected by bethlem myopathy", Biochem Biophys Res Commun, 258, pp.802~807 (1999)