Implication of a novel truncating mutation in titin as a cause of autosomal dominant left ventricular noncompaction
Xue-Qi DONG1
Di ZHANG1
Yi QU1
Yu-Xiao HU1
Chun-Xue YANG1
Tao TIAN1
Nan XU2
Hai-Lun JIANG3
Li ZENG3
Peng-Yan XIA4
Ya-Xin LIU1
Rui LIU3
Xian-Liang ZHOU1
1.Department of Cardiology,Fuwai Hospital,National Center for Cardiovascular Disease,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China2.Department of Echocardiography,Fuwai Hospital,Natio-nal Center for Cardiovascular Disease,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China3.Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China4.State Key Laboratory of Membrane Biology,Institute of Zoology,Chinese Academy of Science,Beijing,China
摘要：BACKGROUND Mutation in the titin gene (TTN) in left ventricular noncompaction (LVNC) has been reported with a highly heterogeneous prevalence, and the molecular mechanisms underlying the pathogenesis of TTN gene mutation are uncharacteri-zed. In the present study, we identified a novel TTN mutation in a pedigree with LVNC and investigated the potential pathogenic mechanism by functional studies. METHODS The whole-genome sequencing with linkage analysis was performed in a 3-generation family affected by autoso-mal dominant LVNC cardiomyopathy. The clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9) technology was used to establish novel truncating mutation in TTN in a rat cardiomyoblast H9C2 cell line in vitro, in which functional studies were carried out and characterized in comparison to its wild-type counterpart. RESULTS A novel truncating mutation TTN p. R2021X was identified as the only plausible disease-causing variant that segreg-ated with disease among the five surviving affected individuals, with an interrogation of the entire genome excluding other po-tential causes. Quantitative reverse transcription-polymerase chain reaction and cellular immunofluorescence supported a haplo-insufficient disease mechanism in titin truncation mutation cardiomyocytes. Further functional studies suggested mitochondrial abnormities in the presence of mutation, including decreased oxygen consumption rate, reduced adenosine triphosphate produc-tion, impaired activity of electron translation chain, and abnormal mitochondrial structure on electron microscopy. Impaired aut-ophagy under electron microscopy accompanied with activation of the Akt-mTORC1 signaling pathway was observed in TTN p. R2021X truncation mutation cardiomyocytes. CONCLUSIONS The TTN p. R2021X mutation has a function in the cause of a highly penetrant familial LVNC. These findings expand the spectrum of titin 's roles in cardiomyopathies and provide novel insight into the molecular basis of titin-truncating variants-associated LVNC.
机标关键词：mutationcausetitinnovelautosomaldominantimplicationleft
论文发表日期：2022-04-28
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：14( 301-314 )