Differential Contributions of Rare and Common, Coding and Noncoding Ret Mutations to Multifactorial Hirschsprung Disease Liability
Differential Contributions of Rare and Common, Coding and Noncoding Ret Mutations to Multifactorial Hirschsprung Disease Liability
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DOI：
10.1016/j.ajhg.2010.06.007
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发表时间：
2010-07-09
影响因子：
9.8
通讯作者：
Chakravarti, Aravinda
中科院分区：
文献类型：
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作者：
Emison, Eileen Sproat;Garcia-Barcelo, Merce;Chakravarti, Aravinda
先天性巨结肠症（HSCR）的主要基因编码受体酪氨酸激酶RET。在一项针对690名欧洲人和192名中国血统先证者及其父母或对照的研究中，我们证明了来自C -> T等位基因的>4倍易感性的普遍性（rs 2435357：欧洲血统中p = 3.9 x 10（-43）;中国样本中p = 1.1 x 10（-21）），该等位基因可能在内含子RET增强子MCS+9.7中出现过一次。通过体外试验，我们现在表明T变体破坏了MCS+9.7内的SOX 10结合位点，从而损害RET反式激活。T等位基因在欧洲/中国血统个体中的对照频率为20%-30%/47%，病例频率为54%-62%/88%，参与所有形式的HSCR。它与先证者性别（p = 0.13）略有相关，与无神经节细胞症的持续时间（p = 7.6 x 10（-5））和家族性（p = 6.2 x 10（-4））显著相关。增强子变异在常见形式的男性、短片段和单一家族中更常见，而在不太常见和更严重形式的女性、长片段和多重家族中，多个、罕见的编码突变是常态。T变异体还增加了具有罕见RET编码突变的患者的突变率。因此，罕见和常见突变，单独和共同，使HSCR的风险。RET变异体在不同HSCR患者中的分布表明了一种“细胞隐性”遗传模型，其中两种RET等位基因的功能都受到损害。RET等位基因系列及其基因型-表型相关性表明，复杂疾病中变异识别的成功可能在很大程度上取决于研究的患者。
The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C -> T allele (rs2435357: p = 3.9 x 10(-43) in European ancestry; p = 1.1 x 10(-21) in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET transactivation. The T allele, with a control frequency of 20%-30%/47% and case frequency of 54%-62%/88% in European/Chinese-ancestry individuals, is involved in all forms of HSCR. It is marginally associated with proband gender (p = 0.13) and significantly so with length of aganglionosis (p = 7.6 x 10(-5)) and familiality (p = 6.2 x 10(-4)). The enhancer variant is more frequent in the common forms of male, short-segment, and simplex families whereas multiple, rare, coding mutations are the norm in the less common and more severe forms of female, long-segment, and multiplex families. The T variant also increases penetrance in patients with rare RET coding mutations. Thus, both rare and common mutations, individually and together, make contributions to the risk of HSCR. The distribution of RET variants in diverse HSCR patients suggests a "cellular-recessive" genetic model where both RET alleles' function is compromised. The RET allelic series, and its genotype-phenotype correlations, shows that success in variant identification in complex disorders may strongly depend on which patients are studied.