Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I
Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I
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DOI：
10.1001/archneur.62.12.1894
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发表时间：
2005-12-01
影响因子：
--
通讯作者：
Pegoraro, E
中科院分区：
文献类型：
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作者：
Boito, CA;Melacini, P;Pegoraro, E
背景：21 型肢带型肌营养不良症是由 fukutin 相关蛋白基因（FKRP）突变引起的。 FKRP 编码一种推定的糖基转移酶蛋白，该蛋白参与α-肌营养不良聚糖糖基化。 目的：识别 21 型肢带型肌营养不良症患者并得出基因型-表型相关性。 设计：对 214 名表现出与肌营养不良症或病因不明的肌病一致的肌肉组织病理学特征的患者进行了研究。使用重叠聚合酶链反应产物的变性高效液相色谱分析患者 DNA 中的整个 1.5 kb FKRP 编码序列，然后对异源双链体进行直接测序。 结果：通过 FKRP 突变分析鉴定出 13 名肢带型肌营养不良症患者（占所有测试患者的 6%），另外 7 名患者通过家庭筛查鉴定出。鉴定出 6 个错义突变（1 个新突变）。 826C>A核苷酸变化是一种常见的突变，存在于35%的突变染色体中。临床表现包括无症状高CK血症、严重早发性肌营养不良症和轻度迟发性肌营养不良症。扩张型心肌病和通气障碍是常见的特征。观察到显着的家族内和家族间临床变异。结论：FKRP 突变是肢带型肌营养不良症的常见原因。患者呼吸和心功能不全的程度与肌肉受累的严重程度无关。 2 名具有 FKRP 突变的无症状患者的发现表明调节因素可能会改善临床表型。
Background: Limb-girdle muscular dystrophy type 21 is caused by mutations in the fukutin-related protein gene (FKRP). FKRP encodes a putative glycosyltransferase protein that is involved in a-dystroglycan glycosylation.Objectives: To identify patients with limb-girdle muscular dystrophy type 21 and to derive genotype-phenotype correlations.Design: Two hundred fourteen patients who showed muscle histopathologic features consistent with muscular dystrophy or myopathy of unknown etiology were studied. The entire 1.5-kilobase FKRP coding sequence from patient DNA was analyzed using denaturing high-performance liquid chromatography of overlapping polymerase chain reaction products, followed by direct sequencing of heteroduplexes.Results: Thirteen patients with limb-girdle muscular dystrophy type 21 (6% of all patients tested) were identified by FKRP mutation analysis, and 7 additional patients were identified by family screening. Six missense mutations (1 novel) were identified. The 826C>A nucleotide change was a common mutation, present in 35% of the mutated chromosomes. Clinical presentations included asymptomatic hyperCKemia, severe early-onset muscular dystrophy, and mild late-onset muscular dystrophy. Dilated cardiomyopathy and ventilatory impairment were frequent features. Significant intrafamilial and interfamilial clinical variability was observed.Conclusions: FKRP mutations are a frequent cause of limb-girdle muscular dystrophies. The degree of respiratory and cardiac insufficiency in patients did not correlate with the severity of muscle involvement. The finding of 2 asymptomatic patients with FKRP mutations suggests that modulating factors may ameliorate the clinical phenotype.