PMID- 24865491 OWN - NLM STAT- MEDLINE DCOM- 20150129 LR - 20220316 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 15 IP - 6 DP - 2014 May 26 TI - Rare variants in genes encoding MuRF1 and MuRF2 are modifiers of hypertrophic cardiomyopathy. PG - 9302-13 LID - 10.3390/ijms15069302 [doi] AB - 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. FAU - Su, Ming AU - Su M AD - 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. FAU - Wang, Jizheng AU - Wang J AD - 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. FAU - Kang, Lianming AU - Kang L AD - 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. FAU - Wang, Yilu AU - Wang Y AD - Intensive Care Unit, China Meitan General Hospital, Beijing 100028, China. wangyilu0908@163.com. FAU - Zou, Yubao AU - Zou Y AD - 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. FAU - Feng, Xinxing AU - Feng X AD - 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. FAU - Wang, Dong AU - Wang D AD - 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. FAU - Ahmad, Ferhaan AU - Ahmad F AD - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA. ferhaan-ahmad@uiowa.edu. FAU - Zhou, Xianliang AU - Zhou X AD - 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. FAU - Hui, Rutai AU - Hui R AD - 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. FAU - Song, Lei AU - Song L AD - 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. LA - eng GR - U01 HL108642/HL/NHLBI NIH HHS/United States GR - U01HL108642-01/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140526 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Muscle Proteins) RN - 0 (Tripartite Motif Proteins) RN - EC 2.3.2.27 (TRIM63 protein, human) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) SB - IM MH - Adult MH - Cardiomyopathy, Hypertrophic/*genetics/pathology MH - Female MH - Genetic Variation MH - Humans MH - Male MH - Middle Aged MH - Muscle Proteins/*genetics MH - Mutation MH - Myocardium/metabolism/pathology MH - Tripartite Motif Proteins MH - Ubiquitin-Protein Ligases/*genetics PMC - PMC4100095 EDAT- 2014/05/29 06:00 MHDA- 2015/01/30 06:00 PMCR- 2014/06/01 CRDT- 2014/05/29 06:00 PHST- 2014/03/07 00:00 [received] PHST- 2014/04/23 00:00 [revised] PHST- 2014/04/30 00:00 [accepted] PHST- 2014/05/29 06:00 [entrez] PHST- 2014/05/29 06:00 [pubmed] PHST- 2015/01/30 06:00 [medline] PHST- 2014/06/01 00:00 [pmc-release] AID - ijms15069302 [pii] AID - ijms-15-09302 [pii] AID - 10.3390/ijms15069302 [doi] PST - epublish SO - Int J Mol Sci. 2014 May 26;15(6):9302-13. doi: 10.3390/ijms15069302.