Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C
Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C
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DOI：
10.1093/hmg/10.25.2851
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发表时间：
2001-12-01
影响因子：
3.5
通讯作者：
Muntoni, F
中科院分区：
文献类型：
--
作者：
Brockington, M;Yuva, Y;Muntoni, F
肢带型和先天性肌营养不良症（LGMD和CMD）的特征在于骨骼肌无力和营养不良性肌肉变化。CMD的症状发生在生命的最初几个月内，而LGMD则可能发生在儿童晚期，青春期或成年期。我们最近已经证明，fukutin相关蛋白基因（FKRP）在严重形式的CMD（MDC 1C）中发生突变，其特征在于无法行走，腿部肌肉肥大和继发性层粘连蛋白α 2和α-肌营养不良蛋白聚糖缺乏。MDC 1C和LGMD 2 I都映射到染色体19q13.3上的相同区域。为了研究这些是否是等位基因疾病，我们对FKRPin 25个潜在的LGMD 2 I家族进行了突变分析，包括一些具有严重和早发表型的家族。在来自17个家庭的个体中鉴定了突变。在所有研究个体的骨骼肌活检中观察到α-肌营养不良蛋白聚糖表达的可变减少。此外，几例病例显示缺乏层粘连蛋白α 2无论是通过免疫细胞化学或蛋白质印迹。出乎意料的是，来自15个家庭的受影响个体具有相同的C826 A（Leu 276 Ileu）突变，其中包括5个纯合子。连锁分析确定了至少两个可能的单倍型与此突变的连锁不平衡。发生C826 A改变的患者具有临床上不太严重的LGMD 2 I表型，表明这是一种比MDC 1C中发现的破坏性更小的FKRP突变。LGMD 2 I表型的范围从早期表现和Duchenne样病程（包括心肌病）的婴儿到与有利的长期结局相容的较温和表型。
The limb girdle and congenital muscular dystrophies (LGMD and CMD) are characterized by skeletal muscle weakness and dystrophic muscle changes. The onset of symptoms in CMD is within the first few months of life, whereas in LGMD they can occur in late childhood, adolescence or adult life. We have recently demonstrated that the fukutin-related protein gene (FKRP) is mutated in a severe form of CMD (MDC1C), characterized by the inability to walk, leg muscle hypertrophy and a secondary deficiency of laminin alpha2 and alpha -dystroglycan. Both MDC1C and LGMD2I map to an identical region on chromosome 19q13.3. To investigate whether these are allelic disorders, we undertook mutation analysis of FKRPin 25 potential LGMD2I families, including some with a severe and early onset phenotype. Mutations were identified in individuals from 17 families. A variable reduction of alpha -dystroglycan expression was observed in the skeletal muscle biopsy of all individuals studied. In addition, several cases showed a deficiency of laminin alpha2 either by immunocytochemistry or western blotting. Unexpectedly, affected individuals from 15 families had an identical C826A (Leu276Ileu) mutation, including five that were homozygous for this change. Linkage analysis identified at least two possible haplotypes in linkage disequilibrium with this mutation. Patients with the C826A change had the clinically less severe LGMD2I phenotype, suggesting that this is a less disruptive FKRP mutation than those found in MDC1C. The spectrum of LGMD2I phenotypes ranged from infants with an early presentation and a Duchenne-like disease course including cardiomyopathy, to milder phenotypes compatible with a favourable long-term outcome.