title: Rare variants in genes encoding MuRF1 and MuRF2 are modifiers of hypertrophic cardiomyopathy.
abstract: Modifier genes contribute to the diverse clinical manifestations of hypertrophic cardiomyopathy (HCM), but are still largely unknown. Muscle ring finger (MuRF) proteins are a class of muscle-specific ubiquitin E3-ligases that appear to modulate cardiac mass and function by regulating the ubiquitin-proteasome system. In this study we screened all the three members of the MuRF family, MuRF1, MuRF2 and MuRF3, in 594 unrelated HCM patients and 307 healthy controls by targeted resequencing. Identified rare variants were confirmed by capillary Sanger sequencing. The prevalence of rare variants in both MuRF1 and MuRF2 in HCM patients was higher than that in control subjects (MuRF1 13/594 (2.2%) vs. 1/307 (0.3%), p = 0.04; MuRF2 22/594 (3.7%) vs. 2/307 (0.7%); p = 0.007). Patients with rare variants in MuRF1 or MuRF2 were younger (p = 0.04) and had greater maximum left ventricular wall thickness (p = 0.006) than those without such variants. Mutations in genes encoding sarcomere proteins were present in 19 (55.9%) of the 34 HCM patients with rare variants in MuRF1 and MuRF2. These data strongly supported that rare variants in MuRF1 and MuRF2 are associated with higher penetrance and more severe clinical manifestations of HCM. The findings suggest that dysregulation of the ubiquitin-proteasome system contributes to the pathogenesis of HCM.
authors.affiliation: State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. suming28@163.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Su
authors.affiliation: State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. jzwang@hotmail.com.
authors.forename: Jizheng
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. lianmingkang@126.com.
authors.forename: Lianming
authors.initials: L
authors.lastname: Kang
authors.affiliation: Intensive Care Unit, China Meitan General Hospital, Beijing 100028, China. wangyilu0908@163.com.
authors.forename: Yilu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. zouyb1973@gmail.com.
authors.forename: Yubao
authors.initials: Y
authors.lastname: Zou
authors.affiliation: State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. xinxing_feng@hotmail.com.
authors.forename: Xinxing
authors.initials: X
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. wangdongfw@gmail.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA. ferhaan-ahmad@uiowa.edu.
authors.forename: Ferhaan
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. zhouxianliang0326@hotmail.com.
authors.forename: Xianliang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. huirutai@gmail.com.
authors.forename: Rutai
authors.initials: R
authors.lastname: Hui
authors.affiliation: State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. lsongqd@yahoo.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Song
mesh_terms: D000328:Adult; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases