Li D Y, Toland A E, Boak B B, Atkinson D L, Ensing G J, Morris C A, Keating M T
Cardiology Division, University of Utah Health Sciences Center, Eccles Institute of Human Genetics, Salt Lake City 84112, USA.
Hum Mol Genet. 1997 Jul;6(7):1021-8. doi: 10.1093/hmg/6.7.1021.
Supravalvular aortic stenosis (SVAS) is an inherited obstructive vascular disease that affects the aorta, carotid, coronary and pulmonary arteries. Previous molecular genetic data have led to the hypothesis that SVAS results from mutations in the elastin gene, ELN. In these studies, the disease phenotype was linked to gross DNA rearrangements (35 and 85 kb deletions and a translocation) in three SVAS families. However, gross rearrangements of ELN have not been identified in most cases of autosomal dominant SVAS. To define the spectrum of ELN mutations responsible for this disorder, we refined the genomic structure of human ELN and used this information in mutational analyses. ELN point mutations co-segregate with the disease in four familial cases and are associated with SVAS in three sporadic cases. Two of the mutations are nonsense, one is a single base pair deletion and four are splice site mutations. In one sporadic case, the mutation arose de novo. These data demonstrate that point mutations of ELN cause autosomal dominant SVAS.
主动脉瓣上狭窄（SVAS）是一种遗传性阻塞性血管疾病，可影响主动脉、颈动脉、冠状动脉和肺动脉。先前的分子遗传学数据提出了一个假说，即SVAS是由弹性蛋白基因（ELN）突变引起的。在这些研究中，疾病表型与三个SVAS家族中的大片段DNA重排（35和85 kb缺失以及一次易位）有关。然而，在大多数常染色体显性遗传的SVAS病例中尚未发现ELN的大片段重排。为了确定导致这种疾病的ELN突变谱，我们完善了人类ELN的基因组结构，并将此信息用于突变分析。ELN点突变在四个家族性病例中与疾病共分离，并在三个散发性病例中与SVAS相关。其中两个突变是无义突变，一个是单碱基对缺失，四个是剪接位点突变。在一个散发性病例中，该突变是新发的。这些数据表明，ELN的点突变可导致常染色体显性遗传的SVAS。
