SORBS2 is a genetic factor contributing to cardiac malformation of 4q deletion syndrome patients.
SORBS2 is a genetic factor contributing to cardiac malformation of 4q deletion syndrome patients.
复制标题
SORBS2是导致4q缺失综合征患者心脏畸形的遗传因素。
DOI：
10.7554/elife.67481
复制
发表时间：
2021-06-08
期刊：
影响因子：
7.7
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Liang F;Wang B;Geng J;You G;Fa J;Zhang M;Sun H;Chen H;Fu Q;Zhang X;Zhang Z
染色体4 q缺失是先天性心脏病（CHD）患者中最常见的基因组失衡事件之一。然而，一部分CHD相关的4 q缺失没有已知的CHD基因提示未知的CHD基因在这些区间内。在这里，我们已经表明，SORBS 2，一个4 q间隔基因的敲低，破坏心肌细胞的肌节完整性，并导致人胚胎干细胞分化模型中心肌细胞数量减少。分子分析显示，在SORBS 2敲低的细胞中，第二心脏区域（SHF）标记基因的表达降低，NOTCH和SHH信号转导受损。外源性SHH挽救了SORBS 2敲低诱导的心肌细胞分化缺陷。Sorbs 2-/-小鼠突变体具有房间隔发育不全/发育不全或双房间隔（DAS），其来源于受损的后部SHF，具有类似的表达改变。罕见的SORBS 2变异体在300例CHD患者的队列中显著富集。我们的研究结果表明，SORBS 2是SHF发展的调节因子，其变体有助于CHD发病机制。在Sorbs 2-/-心脏中DAS的存在揭示了这种罕见异常与反常血栓栓塞相关的第一个分子病因。
Chromosome 4q deletion is one of the most frequently detected genomic imbalance events in congenital heart disease (CHD) patients. However, a portion of CHD-associated 4q deletions without known CHD genes suggests unknown CHD genes within these intervals. Here, we have shown that knockdown of SORBS2, a 4q interval gene, disrupted sarcomeric integrity of cardiomyocytes and caused reduced cardiomyocyte number in human embryonic stem cell differentiation model. Molecular analyses revealed decreased expression of second heart field (SHF) marker genes and impaired NOTCH and SHH signaling in SORBS2-knockdown cells. Exogenous SHH rescued SORBS2 knockdown-induced cardiomyocyte differentiation defects. Sorbs2-/- mouse mutants had atrial septal hypoplasia/aplasia or double atrial septum (DAS) derived from impaired posterior SHF with a similar expression alteration. Rare SORBS2 variants were significantly enriched in a cohort of 300 CHD patients. Our findings indicate that SORBS2 is a regulator of SHF development and its variants contribute to CHD pathogenesis. The presence of DAS in Sorbs2-/- hearts reveals the first molecular etiology of this rare anomaly linked to paradoxical thromboembolism.
影响因子：
12.3
作者：
Barriot R;Breckpot J;Thienpont B;Brohée S;Van Vooren S;Coessens B;Tranchevent LC;Van Loo P;Gewillig M;Devriendt K;Moreau Y
通讯作者：
Moreau Y