Prenatal Diagnosis Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; Department of Obstetrics and Gynecology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; Research Department of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Eur J Med Genet. 2021 Nov;64(11):104314. doi: 10.1016/j.ejmg.2021.104314. Epub 2021 Sep 1.
Atrial septal defect, secundum (ASD Ⅱ, OMIM: 603642) is the second common congenital heart defect (CHD) in China. However, the genetic etiology of familial ASD II remains elusive.
Using whole-exome sequencing (WES) and Sanger sequencing, we identified a novel myosin heavy chain 6 (MYH6) gene insertion variation, NM_002471.3: c.5465_5470dup (Arg1822_Glu1823dup), in a large Chinese Han family with ASD II. The variant Arg1822_Glu1823dup co-segregated with the disease in this family with autosomal dominant inheritance. The insertion variant located in the coiled-coil domain of the MYH6 protein, which is highly conserved across homologous myosin proteins and species. In transfected myoblast C2C12 cell lines, the MYH6 Arg1822_Glu1823dup variant significantly impaired myofibril formation and increased apoptosis but did not significantly reduce cell viability. Furthermore, molecular simulations revealed that the Arg1822_Glu1823dup variant impaired the myosin α-helix, increasing the stability of the coiled-coil myosin dimer, suggesting that this variant has an effect on the coiled-coil domain self-aggregation. These findings indicate that Arg1822_Glu1823dup variant plays a crucial role in the pathogenesis of ASD II.
Our findings expand the spectrum of MYH6 variations associated with familial ASD II and may provide a molecular basis in genetic counseling and prenatal diagnosis for this Chinses family.
房间隔缺损，继发孔型（ASD Ⅱ，OMIM：603642）是中国第二常见的先天性心脏病（CHD）。然而，家族性 ASD Ⅱ的遗传病因仍不清楚。
我们使用全外显子组测序（WES）和 Sanger 测序，在一个带有 ASD Ⅱ的大型汉族家族中发现了一个新的肌球蛋白重链 6（MYH6）基因插入变异，NM_002471.3：c.5465_5470dup（Arg1822_Glu1823dup）。该变体 Arg1822_Glu1823dup 与该家族的常染色体显性遗传疾病共分离。插入变异位于 MYH6 蛋白的卷曲螺旋结构域中，该结构域在同源肌球蛋白蛋白和物种中高度保守。在转染的肌母细胞 C2C12 细胞系中，MYH6 Arg1822_Glu1823dup 变体显著损害肌原纤维形成并增加细胞凋亡，但对细胞活力没有显著降低。此外，分子模拟表明 Arg1822_Glu1823dup 变体破坏了肌球蛋白α螺旋，增加了卷曲螺旋肌球蛋白二聚体的稳定性，表明该变体对卷曲螺旋结构域的自我聚集有影响。这些发现表明 Arg1822_Glu1823dup 变体在 ASD Ⅱ的发病机制中起关键作用。
我们的发现扩展了与家族性 ASD Ⅱ相关的 MYH6 变异谱，并可为该中国家族的遗传咨询和产前诊断提供分子基础。
