title: Thymopoietin (lamina-associated polypeptide 2) gene mutation associated with dilated cardiomyopathy.
abstract: Thymopoietin or TMPO (indicated by its alternative gene symbol, LAP2, in this work) has been proposed as a candidate disease gene for dilated cardiomyopathy (DCM), since a LAP2 product associates with nucleoplasmic lamins A/C, which are encoded by the DCM gene LMNA. We developed a study to screen for genetic mutations in LAP2 in a large collection of DCM patients and families. A total of 113 subjects from 88 families (56 with familial DCM (FDC) and 32 with sporadic DCM) were screened for LAP2 mutations using denaturing high-performance liquid chromatography and sequence analysis. We found a single putative mutation affecting the LAP2alpha isoform in one FDC pedigree. The mutation predicts an Arg690Cys substitution (c.2068C>T; p.R690C) located in the C-terminal domain of the LAP2alpha protein, a region that is known to interact with lamin A/C. RT-PCR, Western blot analyses, and immunolocalization revealed low-level LAP2alpha expression in adult cardiac muscle, and localization to a subset of nuclei. Mutated Arg690Cys LAP2alpha expressed in HeLa cells localized to the nucleoplasm like wild-type LAP2alpha, with no effect on peripheral and nucleoplasmic lamin A distribution. However, the in vitro interaction of mutated LAP2alpha with the pre-lamin A C-terminus was significantly compromised compared to the wild-type protein. LAP2 mutations may represent a rare cause of DCM. The Arg690Cys mutation altered the observed LAP2alpha interaction with A-type lamins. Our finding implicates a novel nuclear lamina-associated protein in the pathogenesis of genetic forms of dilated cardiomyopathy.
authors.affiliation: CU-Cardiovascular Institute, University of Colorado Health Sciences Center, Denver, Colorado, USA. Matthew.Taylor@UCHSC.edu
authors.forename: Matthew R G
authors.initials: MR
authors.lastname: Taylor
authors.forename: Dobromir
authors.initials: D
authors.lastname: Slavov
authors.forename: Andreas
authors.initials: A
authors.lastname: Gajewski
authors.forename: Sylvia
authors.initials: S
authors.lastname: Vlcek
authors.forename: Lisa
authors.initials: L
authors.lastname: Ku
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Fain
authors.forename: Elisa
authors.initials: E
authors.lastname: Carniel
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Lenarda
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sinagra
authors.forename: Mark M
authors.initials: MM
authors.lastname: Boucek
authors.forename: Jean
authors.initials: J
authors.lastname: Cavanaugh
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Graw
authors.forename: Patsy
authors.initials: P
authors.lastname: Ruegg
authors.forename: Jennie
authors.initials: J
authors.lastname: Feiger
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhu
authors.forename: Debra A
authors.initials: DA
authors.lastname: Ferguson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
authors.forename: Josef
authors.initials: J
authors.lastname: Gotzmann
authors.forename: Roland
authors.initials: R
authors.lastname: Foisner
authors.forename: Luisa
authors.initials: L
authors.lastname: Mestroni
mesh_terms: D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002853:Chromatography, Liquid; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D020125:Mutation, Missense; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010375:Pedigree; D020033:Protein Isoforms / Q000235:genetics; D017434:Protein Structure, Tertiary
chemical_list: D004268:DNA-Binding Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; D020033:Protein Isoforms; C093413:lamina-associated polypeptide 2