Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy Journal Article

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Authors: Helms, A. S.; Davis, F. M.; Coleman, D.; Bartolone, S. N.; Glazier, A. A.; Pagani, F.; Yob, J. M.; Sadayappan, S; Pedersen, E.; Lyons, R.; Westfall, M. V.; Jones, R.; Russell, M. W.; Day, S. M.
Article Title: Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy
Abstract: BACKGROUND: Heterozygous mutations in sarcomere genes in hypertrophic cardiomyopathy (HCM) are proposed to exert their effect through gain of function for missense mutations or loss of function for truncating mutations. However, allelic expression from individual mutations has not been sufficiently characterized to support this exclusive distinction in human HCM. METHODS AND RESULTS: Sarcomere transcript and protein levels were analyzed in septal myectomy and transplant specimens from 46 genotyped HCM patients with or without sarcomere gene mutations and 10 control hearts. For truncating mutations in MYBPC3, the average ratio of mutant:wild-type transcripts was approximately 1:5, in contrast to approximately 1:1 for all sarcomere missense mutations, confirming that nonsense transcripts are uniquely unstable. However, total MYBPC3 mRNA was significantly increased by 9-fold in HCM samples with MYBPC3 mutations compared with control hearts and with HCM samples without sarcomere gene mutations. Full-length MYBPC3 protein content was not different between MYBPC3 mutant HCM and control samples, and no truncated proteins were detected. By absolute quantification of abundance with multiple reaction monitoring, stoichiometric ratios of mutant sarcomere proteins relative to wild type were strikingly variable in a mutation-specific manner, with the fraction of mutant protein ranging from 30% to 84%. CONCLUSIONS: These results challenge the concept that haploinsufficiency is a unifying mechanism for HCM caused by MYBPC3 truncating mutations. The range of allelic imbalance for several missense sarcomere mutations suggests that certain mutant proteins may be more or less stable or incorporate more or less efficiently into the sarcomere than wild-type proteins. These mutation-specific properties may distinctly influence disease phenotypes.
Journal Title: Circulation.Cardiovascular genetics
Volume: 7
Issue: 4
ISSN: 1942-3268; 1942-3268
Publisher: American Heart Association, Inc  
Journal Place: United States
Date Published: 2014
Start Page: 434
End Page: 443
Language: eng
DOI/URL:

10.1161/CIRCGENETICS.113.000448
Notes: LR: 20150801; CI: (c) 2014; GR: K02HL114749/HL/NHLBI NIH HHS/United States; GR: R01 HL093338/HL/NHLBI NIH HHS/United States; GR: R01HL093338/HL/NHLBI NIH HHS/United States; GR: R01HL105826/HL/NHLBI NIH HHS/United States; GR: T32 HL007853/HL/NHLBI NIH HHS/United States; JID: 101489144; 0 (Carrier Proteins); 0 (RNA, Messenger); 0 (myosin-binding protein C); NIHMS614378; OID: NLM: NIHMS614378; OID: NLM: PMC4254656; OTO: NOTNLM; 2014/07/16 [aheadofprint]; ppublish