ALK2 mutation in a patient with Down's syndrome and a congenital heart defect
ALK2 mutation in a patient with Down's syndrome and a congenital heart defect
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DOI：
10.1038/ejhg.2010.224
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发表时间：
2011-04-01
影响因子：
5.2
通讯作者：
Bakkers, Jeroen
中科院分区：
文献类型：
--
作者：
Joziasse, Irene C.;Smith, Kelly A.;Bakkers, Jeroen
唐氏综合征(DS)是由额外的21号染色体拷贝(21三体)引起的，常与先天性心脏病(CHDS)相关。虽然21号染色体序列剂量的增加可能是心脏缺陷的部分原因，但只有一部分DS患者表现出先天性心脏缺陷(出生患病率为40%-60%)。通过对房室间隔缺损患者进行大候选基因测序筛选，在1例DS和1例原始型房间隔缺损患者中发现了骨形态发生蛋白(BMP)I型受体ALK2和另外两个基因的替换。对ALK2受体细胞质结构域的结构模拟表明，H286非常接近激酶域的核苷酸结合部位。我们通过体外和体内实验研究了P.His286Asp替换是否改变了ALK2的功能。通过BMP特异性转录反应分析，P.His286Asp变异体表现出功能活性受损。此外，通过将RNA注射到斑马鱼胚胎中，与野生型ALK2相比，在体内观察到了轻微的显性干扰活性。这些数据表明，在DS背景下，ALK2介导的BMP信号减少可能与CHDS有关。《欧洲人类遗传学杂志》(2011年)19389393期；DOI：10.1038/ejhg.2010.224；2011年1月19日在线发布
Down's syndrome (DS), resulting from an additional copy of chromosome 21 (trisomy 21), is frequently associated with congenital heart defects (CHDs). Although the increased dosage of chromosome 21 sequences is likely to be part of the etiology of cardiac defects, only a proportion of DS patients exhibit a congenital heart defect (birth prevalence 40-60%). Through a large-candidate gene-sequencing screen in patients with atrioventricular septal defects, substitutions were identified in bone morphogenetic protein (BMP) type I receptor ALK2 and two other genes in a patient with DS and a primum-type atrial septal defect. Structural modeling of the cytoplasmic domain of the ALK2 receptor suggests that H286 is in close proximity to the nucleotide-binding site of the kinase domain. We investigated whether this p.His286Asp substitution altered ALK2 function by using both in vitro as well as in vivo assays. The p.His286Asp variant demonstrated impaired functional activity as measured by BMP-specific transcriptional response assays. Furthermore, mild dominant-interfering activity was observed in vivo compared with wild-type ALK2 as determined by RNA injection into zebrafish embryos. These data indicate that in the context of a DS background, ALK2-mediated reduction of BMP signaling may contribute to CHDs. European Journal of Human Genetics (2011) 19, 389-393; doi:10.1038/ejhg.2010.224; published online 19 January 2011