Gualandi F, Urciuolo A, Martoni E, Sabatelli P, Squarzoni S, Bovolenta M, Messina S, Mercuri E, Franchella A, Ferlini A, Bonaldo P, Merlini L
Dipartimento di Medicina Sperimentale e Diagnostica, Sezione di Genetica Medica, Università di Ferrara, Ferrara, Italia 44100.
Neurology. 2009 Dec 1;73(22):1883-91. doi: 10.1212/WNL.0b013e3181c3fd2a.
Bethlem myopathy is a well-defined clinical entity among collagen VI disorders, featuring proximal muscle weakness and contractures of the fingers, wrists, and ankles. It is an early-onset, slowly progressive, and relatively mild disease, invariably associated to date with heterozygous dominant mutations in the 3 collagen VI genes. We have characterized the clinical, laboratory, and genetic features of autosomal recessive Bethlem myopathy in 2 unrelated patients.
This study is based on clinical, histochemical, immunocytochemical, and electron microscope evaluation of the muscle and dermal fibroblasts, CT imaging of the muscles, and biochemical and molecular analysis.
Both patients carry a truncating COL6A2 mutation (Q819X; R366X) associated with missense changes in the partnering allele lying within the C2 domain of the alpha2(VI) chain (D871N; R843W-R830Q). They show decreased amounts of collagen VI in the basal lamina of muscle fibers and in dermal fibroblast cultures and altered behavior of collagen VI tetramers. Biochemical studies supported the pathogenic effect of identified amino acid substitutions, which involve strictly conserved residues.
The reported patients illustrate the occurrence of Bethlem myopathy with a recessive mode of inheritance. This observation completes the hereditary pattern in collagen VI myopathies with both Ullrich congenital muscular dystrophy and Bethlem myopathy underlined by either recessive or dominant effecting mutations. This finding has relevant implications for genetic counseling and molecular characterization of patients with Bethlem myopathy, as well as for genotype-phenotype correlations in collagen VI disorders.
贝斯勒姆肌病是胶原VI型疾病中一种明确的临床实体，其特征为近端肌无力以及手指、手腕和脚踝挛缩。它是一种早发性、进展缓慢且相对较轻的疾病，迄今为止总是与3种胶原VI基因的杂合显性突变相关。我们已对2例无亲缘关系的常染色体隐性贝斯勒姆肌病患者的临床、实验室和基因特征进行了描述。
本研究基于对肌肉和皮肤成纤维细胞的临床、组织化学、免疫细胞化学及电子显微镜评估、肌肉的CT成像以及生化和分子分析。
两名患者均携带一种截短型COL6A2突变（Q819X；R366X），该突变与位于α2(VI)链C2结构域内的配对等位基因中的错义变化相关（D871N；R843W-R830Q）。他们在肌纤维基膜和皮肤成纤维细胞培养物中的胶原VI含量降低，且胶原VI四聚体的行为发生改变。生化研究支持了所鉴定氨基酸替代的致病作用，这些替代涉及严格保守的残基。
所报道的患者说明了贝斯勒姆肌病隐性遗传模式的发生。这一观察结果完善了胶原VI型肌病的遗传模式，其中乌尔里希先天性肌营养不良和贝斯勒姆肌病均由隐性或显性效应突变所突显。这一发现对于贝斯勒姆肌病患者的遗传咨询和分子特征分析，以及胶原VI型疾病的基因型-表型相关性具有重要意义。
