DMD Trp3X nonsense mutation associated with a founder effect in North American families with mild Becker muscular dystrophy
DMD Trp3X nonsense mutation associated with a founder effect in North American families with mild Becker muscular dystrophy
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DOI：
10.1016/j.nmd.2009.08.010
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发表时间：
2009-11-01
影响因子：
2.8
通讯作者：
Weiss, Robert B.
中科院分区：
文献类型：
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作者：
Flanigan, Kevin M.;Dunn, Diane M.;Weiss, Robert B.
DMD基因复发性外显子1无义突变p.Trp3X (c.9G > A)，首次在一名20岁前无症状且行走至62岁的先证患者中被确定。随后确定了另外六种携带p.Trp3X突变的不相关品种，其中五种来自北美，一种来自意大利。在七种中的六种中，先证者在儿童时期偶然出现在其他疾病背景下检测到的肌酸激酶水平升高，或在伴有或不伴有横纹肌溶解的痉挛情况下。高密度SNP基因分型的遗传分析表明，6个北美家庭共有一个围绕p.Trp3X等位基因的3.7 Mbp单倍型，这表明这是这些个体的创始突变。创始单倍型的大小和共享全基因组片段的结构表明，这种突变的最小年龄为60代。第一个DMD奠基者突变的发现，与轻度贝克表型相关，表明应使用改进的基因组分析重新检查亚形态营养不良蛋白突变的患病率。(C) 2009 Elsevier B.V.版权所有
A recurrent exon 1 nonsense mutation in the DMD gene, p.Trp3X (c.9G > A), was first ascertained in a proband with no symptoms until age 20 and who walked until the age of 62. Six other unrelated kindreds carrying a p.Trp3X mutation were subsequently ascertained, five from North America and one from Italy. in six of the seven kindreds, the proband presented in childhood incidental to elevated creatine kinase levels detected in the context of other illnesses, or in the setting of cramps with or without rhabdomyolysis. Genetic analysis by high density SNP genotyping demonstrates that the six North American families share a 3.7 Mbp haplotype surrounding the p.Trp3X allele, signifying that this is a founder mutation in these individuals. The size of the founder haplotype and the structure of shared genome-wide segments suggests that the minimal age of this mutation is >6 generations. The discovery of the first DMD founder mutation, associated with a mild Becker phenotype, suggests that the prevalence of hypomorphic dystrophin mutations should be re-examined with the use of improved genomic analysis. (C) 2009 Elsevier B.V. All rights reserved.