Shufang Huang1, Yueheng Wu2, Shaoxian Chen2, Yongchao Yang3, Yonghua Wang1, Haiping Wang1, Ping Li1, Jian Zhuang3, Yu Xia4. 1. 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. 2. 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. 3. Department of Cardiovascular Surgery of Guangdong Provincial Cardiovascular Disease Institute, 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. 4. Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China; The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China. Electronic address: line_user@163.com.
Abstract
OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.
OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.
Authors: Li Jia; Dai Limeng; Tan Xiaoyin; Wang Junwen; Zhu Xintong; Xiong Gang; Bai Yun; Guo Hong Journal: Stem Cell Rev Rep Date: 2022-07-02 Impact factor: 5.739
Authors: Melissa Anfinson; Robert H Fitts; John W Lough; Jeanne M James; Pippa M Simpson; Stephanie S Handler; Michael E Mitchell; Aoy Tomita-Mitchell Journal: J Cardiovasc Dev Dis Date: 2022-05-03