Infantile Muscular Dystrophy in Canadian Aboriginals Is an αB-Crystallinopathy
Infantile Muscular Dystrophy in Canadian Aboriginals Is an αB-Crystallinopathy
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DOI：
10.1002/ana.22331
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发表时间：
2011-05-01
影响因子：
11.2
通讯作者：
Selcen, Duygu
中科院分区：
文献类型：
--
作者：
Del Bigio, Marc R.;Chudley, Albert E.;Selcen, Duygu
目的：在加拿大土著人中描述了一种隐性传播的致死性高渗性婴儿肌营养不良症。受影响的婴儿出现进行性肢体和轴向肌肉僵硬，并发展为严重的呼吸功能不全，大多数在出生一岁时死亡。方法：我们对12例患者进行了组织化学、免疫细胞化学、电子显微镜和分子遗传学研究。结果：常规组织化学和电子显微镜检查提示肌原纤维肌病。因此，我们寻找MFM典型的多种蛋白的异位表达。使用针对整个蛋白质的单抗，所有纤维都不表达αB-晶体蛋白(αBC)。然而，一种针对αBC前10个残基的单抗对异常纤维部分进行了免疫染色。为了寻找这条线索，我们在8名患者的DNA样本中寻找阿尔法BC(CryAB)基因的突变。它们都含有一个纯合子缺失，c.60c，预测在第21位密码子的Ser到Ala的改变和23个错义残基(p.Ser21AlafsX24)后的一个终止密码子。临床上未受影响的父母是这种突变的杂合子。解释：CryAB中的纯合子c.60delC精确地指出了加拿大土著人致命的婴儿高张力性肌营养不良的遗传基础。MFMS通常通过显性遗传传递，但在这种疾病中，父母的表型是通过高度截断的无功能突变基因产物的有限表达来挽救的。严重的患者表型是由于明显的亚型等位基因的纯合所致。Ann Neurol 2011；69：866-871
Objective: A recessively transmitted fatal hypertonic infantile muscular dystrophy has been described in Canadian aboriginals. The affected infants present with progressive limb and axial muscle stiffness and develop severe respiratory insufficiency, and most die in the first year of life. We sought to determine the genetic basis of this disease.Methods: We performed histochemical, immunocytochemical, electron microscopy, and molecular genetic studies in a cohort of 12 patients affected by this disease.Results: Conventional histochemical and electron microscopy studies suggested myofibrillar myopathy (MFM). Therefore, we searched for ectopic expression of multiple proteins typical of MFM. Alpha B-crystallin (alpha BC) expression was absent from all fibers using a monoclonal antibody raised against the entire protein. However, a monoclonal antibody directed against the first 10 residues of alpha BC immunostained portions of abnormal fibers. Pursuing this clue, we searched for mutations in the gene for alpha BC (CRYAB) in available DNA samples of 8 patients. All harbored a homozygous deletion, c.60C, predicting a Ser to Ala change at codon 21 and a stop codon after 23 missense residues (p.Ser21AlafsX24). Clinically unaffected parents were heterozygous for this mutation.Interpretation: The homozygous c.60delC in CRYAB pinpoints the genetic basis of the fatal infantile hypertonic muscular dystrophy of Canadian aboriginals. MFMs are typically transmitted by dominant inheritance, but in this disease the parental phenotype is rescued by limited expression of the highly truncated nonfunctional mutant gene product. The severe patient phenotype is due to homozygosity for the markedly hypomorphic allele. ANN NEUROL 2011; 69: 866-871