Non-synonymous variants in pre-B cell leukemia homeobox (PBX) genes are associated with congenital heart defects.
Non-synonymous variants in pre-B cell leukemia homeobox (PBX) genes are associated with congenital heart defects.
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DOI：
10.1016/j.ejmg.2012.02.002
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发表时间：
2012-04
影响因子：
1.9
通讯作者：
Bowles NE
中科院分区：
文献类型：
--
作者：
Arrington CB;Dowse BR;Bleyl SB;Bowles NE
先天性心脏畸形是最常见的出生缺陷之一，大多数被认为是多基因/多因素的。最近，缺乏前b细胞白血病转录同源盒（PBX）基因的小鼠被创造出来并发现有一系列心室流出道（OFT）畸形。因此，我们筛选了95例先天性心脏缺陷患者，包括OFT畸形，用于编码PBX蛋白的基因变异，以及相互作用蛋白。采用聚合酶链反应扩增PBX1-4、PKNOX1、PKNOX2、MEIS1-3和PBXIP1的编码外显子，并在Lightscanner上分析产物。对熔点异常样品进行DNA测序分析。在5个蛋白（Pbx3, Pbx4, Meis1， Meis3和Pknox1）中鉴定出7个非同义变异（6个新变异和1个SNP）。Pbx3的一个变体p.A136V位于一个高度保守的聚丙氨酸通道中，预计是有害的。该变异在5.2%的心脏缺陷患者中存在，而在380名种族和种族匹配的对照组中为1.3% （P<0.05）。据预测，其他变异都不会造成损害。总之，我们的研究结果支持Pbx3 Ala136Val变异是先天性心脏缺陷的修饰因子或风险等位基因，并暗示pbx相关基因是冠心病的候选者，特别是那些影响心脏流出道的基因。
Congenital cardiac malformations are one of the most common birth defects and most are believed to be multigenic/multifactorial in nature. Recently mice lacking Pre-B cell leukemia transcription homeobox (PBX) genes were created and found to have a range of ventricular outflow tract (OFT) malformations. Therefore, we screened 95 patients with congenital heart defects, including OFT malformations, for variants in genes encoding PBX proteins, as well as interacting proteins. The coding exons of PBX1-4, PKNOX1, PKNOX2, MEIS1-3, and PBXIP1 were amplified by polymerase chain reaction and the products analyzed on a Lightscanner. Samples with abnormal melting profiles were analyzed by DNA sequencing. Seven non-synonymous variants (6 novel and 1 SNP) were identified in 5 proteins (Pbx3, Pbx4, Meis1, Meis3 and Pknox1). One Pbx3 variant, p.A136V, is located in a highly conserved polyalanine tract and predicted to be deleterious. This variant was present in 5.2% of heart defect patients compared with 1.3% of 380 race- and ethnicity-matched controls (P<0.05). None of the other variants were predicted to be damaging. In conclusion, our results support the Pbx3 Ala136Val variant as a modifier or risk allele for congenital heart defects and implicate PBX-related genes as candidates for CHD, especially those affecting the cardiac outflow tract.