Elastin: mutational spectrum in supravalvular aortic stenosis
Elastin: mutational spectrum in supravalvular aortic stenosis
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DOI：
10.1038/sj.ejhg.5200564
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发表时间：
2000-12-01
影响因子：
5.2
通讯作者：
Tassabehji, M
中科院分区：
文献类型：
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作者：
Metcalfe, K;Rucka, AK;Tassabehji, M
主动脉瓣上狭窄（SVAS）是一种先天性升主动脉狭窄，可作为常染色体显性疾病或威廉姆斯综合征的一个组成部分偶尔发生。SVAS是由易位、大缺失和破坏7q11.23上弹性蛋白基因（ELN）的点突变引起的。已知弹性蛋白的功能性半合子是累及ELN的大体染色体异常患者中SVAS的原因。然而，点突变的致病机制尚不清楚。对100例诊断为SVAS且核型正常的患者进行弹性蛋白基因突变筛查，以进一步阐明该疾病的分子病理学。在35例患者中检测到与血管疾病相关的突变，包括无义突变、移码突变、翻译起始突变和剪接位点突变。这四个错义突变是第一个与SVAS相关的错义突变。在这里，我们描述了发生在家族性和散发性SVAS的突变谱，并试图定义参与SVAS的突变机制。SVAS在家族中表现出不同的遗传率，但在某些情况下，这种疾病的进行性，使得分子病变的鉴定对未来的预防性治疗很重要。
Supravalvular aortic stenosis (SVAS) is a congenital narrowing of the ascending aorta which can occur sporadically, as an autosomal dominant condition, or as one component of Williams syndrome. SVAS is caused by translocations, gross deletions and point mutations that disrupt the elastin gene (ELN) on 7q11.23. Functional hemizygosity for elastin is known to be the cause of SVAS in patients with gross chromosomal abnormalities involving ELN. However, the pathogenic mechanisms of point mutations are less clear. One hundred patients with diagnosed SVAS and normal karyotypes were screened for mutations in the elastin gene to further elucidate the molecular pathology of the disorder. Mutations associated with the vascular disease were detected in 35 patients, and included nonsense, frameshift, translation initiation and splice site mutations. The four missense mutations identified are the first of this type to be associated with SVAS. Here we describe the spectrum of mutations occurring in familial and sporadic SVAS and attempt to define the mutational mechanisms involved in SVAS. SVAS shows variable penetrance within families but the progressive nature of the disorder in some cases, makes identification of the molecular lesions important for future preventative treatments.