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.
  
  
  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 ≈1:5, in contrast to ≈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.
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: Adam S
authors.initials: AS
authors.lastname: Helms
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: Frank M
authors.initials: FM
authors.lastname: Davis
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: David
authors.initials: D
authors.lastname: Coleman
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Bartolone
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Glazier
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: Francis
authors.initials: F
authors.lastname: Pagani
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Yob
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Sadayappan
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: Ellen
authors.initials: E
authors.lastname: Pedersen
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: Robert
authors.initials: R
authors.lastname: Lyons
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: Margaret V
authors.initials: MV
authors.lastname: Westfall
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: Richard
authors.initials: R
authors.lastname: Jones
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.).
authors.forename: Mark W
authors.initials: MW
authors.lastname: Russell
authors.affiliation: From the Departments of Internal Medicine (A.S.H., F.D., D.C., S.B., J.M.Y., S.M.D.), Molecular and Integrative Physiology (A.A.G., M.V.W.), Cardiac Surgery (F.P., M.V.W.), Sequencing Core (E.P., R.L.), and Pediatrics (M.W.R.), University of Michigan, Ann Arbor; Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S.S.); and MS Bioworks, Ann Arbor, MI (R.J.). sday@umich.edu.
authors.forename: Sharlene M
authors.initials: SM
authors.lastname: Day
mesh_terms: D000483:Alleles; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004452:Echocardiography; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism; D040901:Proteomics; D012333:RNA, Messenger / Q000378:metabolism; D012518:Sarcomeres / Q000235:genetics*; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D012333:RNA, Messenger; D000099163:Myosin Binding Protein C
keywords: cardiomyopathy, hypertrophic; gene expression; gene expression regulation; humans; proteomics; sarcomeres