Demir Ercan, Sabatelli Patrizia, Allamand Valérie, Ferreiro Ana, Moghadaszadeh Behzad, Makrelouf Mohamed, Topaloglu Haluk, Echenne Bernard, Merlini Luciano, Guicheney Pascale
INSERM U 523, Groupe Hospitalier Pitié-Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris cedex 13, France.
Am J Hum Genet. 2002 Jun;70(6):1446-58. doi: 10.1086/340608. Epub 2002 Apr 24.
Ullrich congenital muscular dystrophy (UCMD) is an autosomal recessive disorder characterized by generalized muscular weakness, contractures of multiple joints, and distal hyperextensibility. Homozygous and compound heterozygous mutations of COL6A2 on chromosome 21q22 have recently been shown to cause UCMD. We performed a genomewide screening with microsatellite markers in a consanguineous family with three sibs affected with UCMD. Linkage of the disease to chromosome 2q37 was found in this family and in two others. We analyzed COL6A3, which encodes the alpha3 chain of collagen VI, and identified one homozygous mutation per family. In family I, the three sibs carried an A-->G transition in the splice-donor site of intron 29 (6930+5A-->G), leading to the skipping of exon 29, a partial reduction of collagen VI in muscle biopsy, and an intermediate phenotype. In family II, the patient had an unusual mild phenotype, despite a nonsense mutation, R465X, in exon 5. Analysis of the patient's COL6A3 transcripts showed the presence of various mRNA species-one of which lacked several exons, including the exon containing the nonsense mutation. The deleted splice variant encodes collagen molecules that have a shorter N-terminal domain but that may assemble with other chains and retain a functional role. This could explain the mild phenotype of the patient who was still ambulant at age 18 years and who showed an unusual combination of hyperlaxity and finger contractures. In family III, the patient had a nonsense mutation, R2342X, causing absence of collagen VI in muscle and fibroblasts, and a severe phenotype, as has been described in patients with UCMD. Mutations in COL6A3 are described in UCMD for the first time and illustrate the wide spectrum of phenotypes which can be caused by collagen VI deficiency.
乌尔里希先天性肌营养不良（UCMD）是一种常染色体隐性疾病，其特征为全身肌肉无力、多个关节挛缩以及远端关节过度伸展。最近研究表明，位于21号染色体21q22的COL6A2基因的纯合和复合杂合突变会导致UCMD。我们对一个有三名患UCMD同胞的近亲家庭进行了微卫星标记全基因组筛查。在这个家庭以及另外两个家庭中发现该疾病与2号染色体2q37连锁。我们分析了编码胶原蛋白VIα3链的COL6A3基因，并在每个家庭中鉴定出一个纯合突变。在家庭I中，三名同胞在第29内含子的剪接供体位点发生了A→G转换（6930 + 5A→G），导致第29外显子缺失，肌肉活检中胶原蛋白VI部分减少，呈现中间型表型。在家庭II中，尽管患者在第5外显子存在无义突变R465X，但具有不寻常的轻度表型。对患者的COL6A3转录本分析显示存在多种mRNA种类，其中一种缺少几个外显子，包括含有无义突变的外显子。缺失剪接变体编码的胶原蛋白分子N端结构域较短，但可能与其他链组装并保留功能作用。这可以解释该患者的轻度表型，该患者18岁时仍能行走，表现出关节过度松弛和手指挛缩的不寻常组合。在家庭III中，患者有一个无义突变R2342X，导致肌肉和成纤维细胞中缺乏胶原蛋白VI，以及如UCMD患者中所描述的严重表型。COL6A3基因的突变在UCMD中首次被描述，说明了胶原蛋白VI缺乏可能导致的广泛表型谱。
