A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk
A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk
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DOI：
10.1038/nature03467
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发表时间：
2005-04-14
期刊：
影响因子：
64.8
通讯作者：
Chakravarti, A
中科院分区：
文献类型：
--
作者：
Emison, ES;McCallion, AS;Chakravarti, A
鉴定导致人类遗传性疾病发生的常见变异仍然是一个重大挑战。先天性巨结肠症（HSCR）是一种多因素的非孟德尔疾病，其中受体酪氨酸激酶RET中罕见的高突变率编码序列突变与其他基因突变共同导致风险。我们已经使用基于家族的关联研究来确定疾病间隔，并将其与比较和功能基因组分析相结合，以优先考虑可以寻找突变的保守和功能元件。我们现在表明，一个常见的非编码RET变异内的一个保守的增强子样序列的内含子1是显着相关的HSCR的易感性，并作出了20倍的贡献，风险比罕见的等位基因。这种突变显著降低了体外增强子活性，具有较低的突变率，在男性和女性中具有不同的遗传效应，并解释了HSCR复杂遗传模式的几个特征。因此，通过关联研究确定的常见低突变率变体可能是常见和罕见疾病的基础。
The identification of common variants that contribute to the genesis of human inherited disorders remains a significant challenge. Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes. We have used family-based association studies to identify a disease interval, and integrated this with comparative and functional genomic analysis to prioritize conserved and functional elements within which mutations can be sought. We now show that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do. This mutation reduces in vitro enhancer activity markedly, has low penetrance, has different genetic effects in males and females, and explains several features of the complex inheritance pattern of HSCR. Thus, common low-penetrance variants, identified by association studies, can underlie both common and rare diseases.