Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin α2 deficiency and abnormal glycosylation of α-dystroglycan
Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin α2 deficiency and abnormal glycosylation of α-dystroglycan
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DOI：
10.1086/324412
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发表时间：
2001-12-01
影响因子：
9.8
通讯作者：
Muntoni, F
中科院分区：
文献类型：
--
作者：
Brockington, M;Blake, DJ;Muntoni, F
先天性肌营养不良症 (CMD) 是一组异质性常染色体隐性遗传疾病，在婴儿期表现为肌肉无力、挛缩和骨骼肌活检显示营养不良性改变。脑结构缺陷，无论是否伴有智力低下，都是几种 CMD 综合征的附加特征。由于 LAMA2 基因突变，大约 40% 的 CMD 患者存在 Merosin (laminin-2) 层粘连蛋白 α2 链原发性缺陷 (MDC1A)。此外，层粘连蛋白 a 2 的继发性缺陷在一些 CMD 综合征中很明显，包括映射到染色体 1q42 的 MDC1B，以及肌眼脑病 (MEB) 和福山 CMD (FCMD)，这两种形式均严重影响大脑。 FCMD 基因编码一种功能未知的蛋白质 fukutin，但序列分析预测它是一种磷酰基配体转移酶。在这里，我们鉴定了 fukutin 蛋白家族新成员的基因（fukutin 相关蛋白 [FKRP]），映射到人类染色体 19q13.3。我们报告了 FKRP 基因的基因组结构及其组织表达模式。已在七个 CMD 家族中发现 FKRP 基因突变，其特征是在生命的第一周内发病，并具有严重的表型，无法行走、肌肉肥大、血清肌酸激酶显着升高以及大脑结构和功能正常。受影响的个体存在继发性层粘连蛋白 a 2 表达缺陷。此外，它们的肌肉α-肌营养不良聚糖的免疫染色显着降低，并且在蛋白质印迹分析中其分子量也降低。我们认为 α-肌营养不良聚糖的这些异常是由其糖基化缺陷引起的，并且是 MDC1C 病理学不可或缺的一部分。
The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders presenting in infancy with muscle weakness, contractures, and dystrophic changes on skeletal-muscle biopsy. Structural brain defects, with or without mental retardation, are additional features of several CMD syndromes. Approximately 40% of patients with CMD have a primary deficiency (MDC1A) of the laminin alpha2 chain of merosin (laminin-2) due to mutations in the LAMA2 gene. In addition, a secondary deficiency of laminin a 2 is apparent in some CMD syndromes, including MDC1B, which is mapped to chromosome 1q42, and both muscle-eye-brain disease (MEB) and Fukuyama CMD (FCMD), two forms with severe brain involvement. The FCMD gene encodes a protein of unknown function, fukutin, though sequence analysis predicts it to be a phosphoryl-ligand transferase. Here we identify the gene for a new member of the fukutin protein family (fukutin related protein [FKRP]), mapping to human chromosome 19q13.3. We report the genomic organization of the FKRP gene and its pattern of tissue expression. Mutations in the FKRP gene have been identified in seven families with CMD characterized by disease onset in the first weeks of life and a severe phenotype with inability to walk, muscle hypertrophy, marked elevation of serum creatine kinase, and normal brain structure and function. Affected individuals had a secondary deficiency of laminin a 2 expression. In addition, they had both a marked decrease in immunostaining of muscle alpha -dystroglycan and a reduction in its molecular weight on western blot analysis. We suggest these abnormalities of alpha -dystroglycan are caused by its defective glycosylation and are integral to the pathology seen in MDC1C.