title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
abstract: Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.
authors.affiliation: The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Enkhsaikhan
authors.initials: E
authors.lastname: Purevjav
authors.forename: Takuro
authors.initials: T
authors.lastname: Arimura
authors.forename: Sibylle
authors.initials: S
authors.lastname: Augustin
authors.forename: Anne-Cecile
authors.initials: AC
authors.lastname: Huby
authors.forename: Ken
authors.initials: K
authors.lastname: Takagi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nunoda
authors.forename: Debra L
authors.initials: DL
authors.lastname: Kearney
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Fumio
authors.initials: F
authors.lastname: Terasaki
authors.forename: Johan M
authors.initials: JM
authors.lastname: Bos
authors.forename: Steve R
authors.initials: SR
authors.lastname: Ommen
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shibata
authors.forename: Megumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Manatsu
authors.initials: M
authors.lastname: Itoh-Satoh
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.forename: Ross T
authors.initials: RT
authors.lastname: Murphy
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Yamanaka
authors.forename: Noboru
authors.initials: N
authors.lastname: Machida
authors.forename: Jeong-Euy
authors.initials: JE
authors.lastname: Park
authors.forename: Peta M A
authors.initials: PM
authors.lastname: Alexander
authors.forename: Robert G
authors.initials: RG
authors.lastname: Weintraub
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kitaura
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D018389:Codon, Nonsense; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D009154:Mutation; D020125:Mutation, Missense; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D011485:Protein Binding; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: C491303:Ankrd1 protein, rat; D018389:Codon, Nonsense; C426225:MYPN protein, human; D009124:Muscle Proteins; D050505:Mutant Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins