Implication of a novel truncating mutation in titin as a cause of autosomal dominant left ventricular noncompaction  

作　　者：Xue-Qi DONG Di ZHANG Yi QU Yu-Xiao HU Chun-Xue YANG Tao TIAN Nan XU Hai-Lun JIANG Li ZENG Peng-Yan XIA Ya-Xin LIU Rui LIU Xian-Liang ZHOU 

机构地区：[1]Department of Cardiology,Fuwai Hospital,National Center for Cardiovascular Disease,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China [2]Department of Echocardiography,Fuwai Hospital,Natio-nal Center for Cardiovascular Disease,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China [3]Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China [4]State Key Laboratory of Membrane Biology,Institute of Zoology,Chinese Academy of Science,Beijing,China

出　　处：《Journal of Geriatric Cardiology》2022年第4期301-314,共14页老年心脏病学杂志（英文版）

基　　金：supported by the National Key Research and Development Program of China(2016 YFC1300100);the National Natural Science Foundation of China(No.81974042);the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019XK320058);the Peking Union Medical College Youth Fund(No.3332018058).

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.

关 键 词：LINKAGE mechanism IMPAIRED 

分 类 号：R542.2[医药卫生—心血管疾病]