Illarioshkin S N, Ivanova-Smolenskaya I A, Tanaka H, Vereshchagin N V, Markova E D, Poleshchuk V V, Lozhnikova S M, Sukhorukov V S, Limborska S A, Slominsky P A, Bulayeva K B, Tsuji S
Department of Neurology, Niigata University, Japan.
Brain. 1996 Dec;119 ( Pt 6):1895-909. doi: 10.1093/brain/119.6.1895.
We describe a unique six-generation, highly consanguineous family originating from an isolated mountainous village in the Russian province of Daghestan. Three separate clinical phenotypes of progressive muscular dystrophy were identified in this large family. Seven patients developed a classical limb-girdle variant of muscular dystrophy (LGMD), with disease onset at 15-30 years and loss of ambulation within a 25-year course. The second group included three patients with a slowly progressive distal myopathy first manifested in the late teens and confined to the tibial and calf muscles. Each of these two phenotypes segregated independently as an autosomal recessive trait, and muscle biopsies showed non-specific myopathic changes. Lastly, two male siblings exhibited an atypical variant of Duchenne muscular dystrophy confirmed by detection of a deletion in the dystrophin gene. To clarify the molecular basis of the polymorphic autosomal recessive form of muscular dystrophy in this kindred, we performed molecular genetic studies on 67 family members and obtained significant evidence for linkage to chromosome 2p. A maximum pairwise lod (logarithm of odds) score of 5.64 was achieved at the zero recombination fraction (i.e. at theta = 0.00) for locus D2S291; multipoint linkage analysis confirmed the most likely location of a mutant gene near D2S291. The patients with LGMD and those with the distal muscular dystrophy phenotype share a common affected homozygous haplotype associated with the same founder chromosome; key recombinants defined D2S286 and D2S292 to be the closest loci flanking the mutant gene. Remarkably, two clinically distinct forms of autosomal recessive muscular dystrophy, LGMD type 2B (LGMD2B) and Miyoshi myopathy, were recently mapped to the same locus. We suggest that all three chromosome 2p-linked conditions may represent allelic disorders, i.e. different phenotypic expressions of a single gene.
我们描述了一个来自俄罗斯达吉斯坦省一个偏远山村的独特的六代高度近亲家族。在这个大家庭中发现了三种不同的进行性肌营养不良临床表型。七名患者患有一种典型的肢带型肌营养不良（LGMD），发病年龄在15至30岁之间，在25年病程内丧失行走能力。第二组包括三名患者，患有缓慢进展的远端肌病，最初在青少年后期出现，局限于胫骨和小腿肌肉。这两种表型均作为常染色体隐性性状独立分离，肌肉活检显示非特异性肌病改变。最后，两名男性同胞表现出一种非典型的杜氏肌营养不良变异型，通过检测肌营养不良蛋白基因中的缺失得以证实。为了阐明这个家族中多态性常染色体隐性形式肌营养不良的分子基础，我们对67名家族成员进行了分子遗传学研究，并获得了与2号染色体p臂连锁的重要证据。在基因座D2S291的零重组率（即θ = 0.00）时，最大成对lod（优势对数）得分为5.64；多点连锁分析证实了突变基因最可能位于D2S291附近。LGMD患者和远端肌病表型患者共享一个与同一奠基者染色体相关的共同受影响纯合单倍型；关键重组体确定D2S286和D2S292是突变基因两侧最接近的基因座。值得注意的是，最近两种临床上不同形式的常染色体隐性肌营养不良，即2B型肢带型肌营养不良（LGMD2B）和三好肌病，被定位到了同一个基因座。我们认为所有这三种与2号染色体p臂连锁的疾病可能代表等位基因疾病，即单个基因的不同表型表达。
