Brockington M, Sewry C A, Herrmann R, Naom I, Dearlove A, Rhodes M, Topaloglu H, Dubowitz V, Voit T, Muntoni F
Neuromuscular Unit, Division of Paediatrics, Obstetrics, and Gynaecology, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, United Kingdom.
Am J Hum Genet. 2000 Feb;66(2):428-35. doi: 10.1086/302775.
We have previously reported an autosomal recessive form of congenital muscular dystrophy, characterized by proximal girdle weakness, generalized muscle hypertrophy, rigidity of the spine, and contractures of the tendo Achilles, in a consanguineous family from the United Arab Emirates. Early respiratory failure resulting from severe diaphragmatic involvement was present. Intellect and the results of brain imaging were normal. Serum creatine kinase levels were grossly elevated, and muscle-biopsy samples showed dystrophic changes. The expression of the laminin-alpha2 chain of merosin was reduced on several fibers, but linkage analysis excluded the LAMA2 locus on chromosome 6q22-23. Here, we report the results of genomewide linkage analysis of this family, by use of homozygosity mapping. In all four affected children, an identical homozygous region was identified on chromosome 1q42, spanning 6-15 cM between flanking markers D1S2860 and D1S2800. We have identified a second German family with two affected children having similar clinical and histopathological features; they are consistent with linkage to the same locus. The cumulative LOD score was 3.57 (straight theta=.00) at marker D1S213. This represents a novel locus for congenital muscular dystrophy. We suggest calling this disorder "CMD1B." The expression of three functional candidate genes in the CMD1B critical region was investigated, and no detectable changes in their level of expression were observed. The secondary reduction in laminin-alpha2 chain in these families suggests that the primary genetic defect resides in a gene coding for a protein involved in basal lamina assembly.
我们之前报道过一个来自阿联酋的近亲家庭中存在一种常染色体隐性先天性肌营养不良，其特征为近端带肌无力、全身肌肉肥大、脊柱僵硬以及跟腱挛缩。严重的膈肌受累导致早期呼吸衰竭。智力及脑部影像学检查结果正常。血清肌酸激酶水平大幅升高，肌肉活检样本显示有营养不良性改变。在多条纤维上，merosin的层粘连蛋白α2链表达降低，但连锁分析排除了6号染色体q22 - 23区域的LAMA2基因座。在此，我们报告通过纯合性定位对该家庭进行全基因组连锁分析的结果。在所有四名患病儿童中，在1号染色体q42区域鉴定出一个相同的纯合区域，位于侧翼标记D1S2860和D1S2800之间，跨度为6 - 15厘摩。我们鉴定出另一个德国家庭，有两名患病儿童具有相似的临床和组织病理学特征；这些特征与同一个基因座的连锁情况相符。在标记D1S213处，累积对数优势分数为3.57（直接θ = 0.00）。这代表了先天性肌营养不良的一个新基因座。我们建议将这种疾病称为“CMD1B”。对CMD1B关键区域中三个功能性候选基因的表达进行了研究，未观察到它们的表达水平有可检测到的变化。这些家庭中层粘连蛋白α2链的继发性降低表明，原发性基因缺陷存在于一个编码参与基膜组装的蛋白质的基因中。
