Thymopoietin (lamina-associated polypeptide 2) gene mutation associated with dilated cardiomyopathy

Hum Mutat. 2005 Dec;26(6):566-74. doi: 10.1002/humu.20250.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiomyopathy, Dilated / genetics*
  • Chromatography, Liquid
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • HeLa Cells
  • Humans
  • Lamin Type A / chemistry
  • Lamin Type A / metabolism
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism
  • Mutation, Missense*
  • Myocardium / cytology
  • Myocardium / metabolism
  • Pedigree
  • Protein Isoforms / genetics
  • Protein Structure, Tertiary


  • DNA-Binding Proteins
  • Lamin Type A
  • Membrane Proteins
  • Protein Isoforms
  • lamina-associated polypeptide 2