Abnormalities in α-dystroglycan expression in MDC1C and LGMD21 muscular dystrophies
Abnormalities in α-dystroglycan expression in MDC1C and LGMD21 muscular dystrophies
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DOI：
10.1016/s0002-9440(10)63160-4
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发表时间：
2004-02-01
影响因子：
6
通讯作者：
Muntoni, F
中科院分区：
文献类型：
--
作者：
Brown, SC;Torelli, S;Muntoni, F
我们最近在先天性肌营养不良1C型（MDC 1C）和肢带型肌营养不良21型（LGMD 21）患者中发现了FKRP基因突变。这些患者的肌膜通常显示α-肌营养不良蛋白聚糖的免疫细胞化学减少。在本报告中，我们扩展了这些观察，并报告了α-肌营养不良蛋白聚糖的残余表达与表型之间的明确相关性。确定了三大类。在临床谱的严重末端（MDC 1C）的患者是无效等位基因和错义突变之间的复合杂合子或携带两个错义突变，并且显示α-肌营养不良蛋白聚糖的严重缺失。具有Duchenne样严重程度的LGMD患者通常α-肌营养不良聚糖中度减少，并且是复合杂合子;介于常见的C826 A（Lcu 276 Ileu）FKRP突变和错义或无义突变之间。轻度LGMD 21的个体几乎总是Leu 276 Ile FKRP突变纯合子，并且在α-肌营养不良蛋白聚糖免疫标记中显示出可变但细微的改变。因此，我们的数据表明α-肌营养不良蛋白聚糖减少、突变和MDC 1C和LGMD 21的临床表型之间存在相关性，这支持肌营养不良蛋白聚糖在这些疾病的发病机制中起核心作用的假设。
We recently identified mutations in the fukutin related protein (FKRP) gene in patients with congenital muscular dystrophy type 1C (MDC1C) and limb girdle muscular dystrophy type 21 (LGMD21). The sarcolemma of these patients typically displays an immunocytochemical reduction of alpha-dystroglycan. in this report we extend these observations and report a clear correlation between the residual expression of alpha-dystroglycan and the phenotype. Three broad categories were identified. Patients at the severe end of the clinical spectrum (MDC1C) were compound heterozygote between a null allele and a missense mutation or carried two missense mutations and displayed a profound depletion of alpha-dystroglycan. Patients with LGMD with a Duchenne-like severity typically had a moderate reduction in alpha-dystroglycan and were compound heterozygotes; between a common C826A (Lcu276Ileu) FKRP mutation and either a missense or a nonsense mutation. Individuals with the milder form of LGMD21 were almost invariably homozygous for the Leu276Ile FKRP mutation and showed a variable but subtle alteration in alpha-dystroglycan immunolabeling. Our data therefore suggest a correlation between a reduction in alpha-dystroglycan, the mutation and the clinical phenotype in MDC1C and LGMD21 which supports the hypothesis that dystroglycan plays a central role in the pathogenesis of these disorders.