Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population.
Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population.
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DOI：
10.1161/circgenetics.111.960872
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Reeves RH
中科院分区：
文献类型：
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作者：
Li H;Cherry S;Klinedinst D;DeLeon V;Redig J;Reshey B;Chin MT;Sherman SL;Maslen CL;Reeves RH
大约一半的唐氏综合征（DS）患者表现出某种形式的先天性心脏病（CHD）。然而，单独的人类21号染色体三体（Hsa21）不足以导致CHD，因为所有DS患者中有一半具有正常心脏，这表明遗传修饰剂与Hsa21上的剂量敏感基因相互作用导致CHD。我们假设，在唐氏综合征和整倍体人群中，在CHD结果出现之前可以耐受的遗传扰动的数量存在一个阈值。我们确定了一组患有DS和完全性房室间隔缺损（AVSD）的个体，并对CHD的两个候选基因CRELD 1和HEY 2进行了测序，CRELD 1与患有或不患有DS的人的AVSD相关，HEY 2的小鼠直系同源物突变时产生间隔缺损。鉴定了几种有害变体，但这些潜在修饰剂的频率较低。我们将这些潜在修饰物的突变形式的小鼠与唐氏综合征的Ts65Dn小鼠模型杂交。将Creld 1或Hey 2的功能丧失等位基因杂交到三体背景上导致CHD的频率显著增加，表明修饰剂和三体基因之间存在相互作用。我们进一步表明，尽管这些突变修饰物中的任何一种本身都是良性的，但当它们一起遗传时，它们会相互作用以影响心脏发育。使用唐氏综合征和先天性心脏病相关基因的小鼠模型，我们证明了一个相互作用的生物学基础，支持一个阈值假设的加性效应的遗传修饰剂在致敏三体人口。
About half of people with Down syndrome (DS) exhibit some form of congenital heart disease (CHD). However, trisomy for human chromosome 21 (Hsa21) alone is insufficient to cause CHD as half of all people with DS have a normal heart, suggesting that genetic modifiers interact with dosage sensitive gene(s) on Hsa21 to result in CHD. We hypothesize that a threshold exists in both Down syndrome and euploid populations for the number of genetic perturbations that can be tolerated before CHD results. We ascertained a group of individuals with DS and complete atrioventricular septal defect (AVSD) and sequenced two candidate genes for CHD, CRELD1, which is associated with AVSD in people with or without DS, and HEY2, whose mouse ortholog produces septal defects when mutated. Several deleterious variants were identified but the frequency of these potential modifiers was low. We crossed mice with mutant forms of these potential modifiers to the Ts65Dn mouse model of Down syndrome. Crossing loss-of-function alleles of either Creld1 or Hey2 onto the trisomic background caused a significant increase in the frequency of CHD, demonstrating an interaction between the modifiers and trisomic genes. We showed further that although either of these mutant modifiers is benign by itself, they interact to affect heart development when inherited together. Using mouse models of Down syndrome and of genes associated with congenital heart disease we demonstrate a biological basis for an interaction that supports a threshold hypothesis for additive effects of genetic modifiers in the sensitized trisomic population.