Lampe A K, Zou Y, Sudano D, O'Brien K K, Hicks D, Laval S H, Charlton R, Jimenez-Mallebrera C, Zhang R-Z, Finkel R S, Tennekoon G, Schreiber G, van der Knaap M S, Marks H, Straub V, Flanigan K M, Chu M-L, Muntoni F, Bushby K M D, Bönnemann C G
Division of Neurology, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Hum Mutat. 2008 Jun;29(6):809-22. doi: 10.1002/humu.20704.
Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), two related conditions of differing severity. BM is a relatively mild dominantly inherited disorder characterized by proximal weakness and distal joint contractures. UCMD was originally regarded as an exclusively autosomal recessive condition causing severe muscle weakness with proximal joint contractures and distal hyperlaxity. We and others have subsequently modified this model when we described UCMD patients with heterozygous in-frame deletions acting in a dominant-negative way. Here we report 10 unrelated patients with a UCMD clinical phenotype and de novo dominant negative heterozygous splice mutations in COL6A1, COL6A2, and COL6A3 and contrast our findings with four UCMD patients with recessively acting splice mutations and two BM patients with heterozygous splice mutations. We find that the location of the skipped exon relative to the molecular structure of the collagen chain strongly correlates with the clinical phenotype. Analysis by immunohistochemical staining of muscle biopsies and dermal fibroblast cultures, as well as immunoprecipitation to study protein biosynthesis and assembly, suggests different mechanisms each for exon skipping mutations underlying dominant UCMD, dominant BM, and recessive UCMD. We provide further evidence that de novo dominant mutations in severe UCMD occur relatively frequently in all three collagen VI chains and offer biochemical insight into genotype-phenotype correlations within the collagen VI-related disorders by showing that severity of the phenotype depends on the ability of mutant chains to be incorporated in the multimeric structure of collagen VI.
编码胶原蛋白VI（COL6A1、COL6A2和COL6A3）的基因突变会导致贝斯勒肌病（BM）和乌尔里希先天性肌营养不良（UCMD），这是两种严重程度不同的相关疾病。BM是一种相对较轻的常染色体显性遗传病，其特征为近端肌无力和远端关节挛缩。UCMD最初被认为是一种纯合子常染色体隐性疾病，会导致严重肌无力，并伴有近端关节挛缩和远端关节过度松弛。随后，我们和其他研究人员修正了这一模型，当时我们描述了一些UCMD患者，其杂合框内缺失以显性负性方式起作用。在此，我们报告了10例具有UCMD临床表型且在COL6A1、COL6A2和COL6A3中存在新生显性负性杂合剪接突变的无关患者，并将我们的研究结果与4例具有隐性作用剪接突变的UCMD患者以及2例具有杂合剪接突变的BM患者进行了对比。我们发现，跳过外显子相对于胶原链分子结构的位置与临床表型密切相关。通过对肌肉活检和皮肤成纤维细胞培养进行免疫组织化学染色分析，以及通过免疫沉淀研究蛋白质生物合成和组装，结果表明，显性UCMD、显性BM和隐性UCMD潜在的外显子跳跃突变各有不同机制。我们进一步证明，严重UCMD中的新生显性突变在所有三条胶原蛋白VI链中相对频繁发生，并通过表明表型的严重程度取决于突变链掺入胶原蛋白VI多聚体结构的能力，为胶原蛋白VI相关疾病的基因型-表型相关性提供了生化方面的见解。
