Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy

Abstract

Based on genetic, histological, and functional evidence, we identified a new gene associated with DCM and observed mutations in 3-4% of cases in a population of European descent.

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

“…As a number of missense mutations in genes encoding for titin and titin-associated proteins have recently been reported to be responsible for DCM, 3,[12][13][14][15][19][20][21][22][23][24][25] we searched in a well-characterized sample of DCM patients for unknown SNPs and/or mutations in the human MYPN and ANKRD1 genes. In order to extend our knowledge on disease-causing mutations in these two proteins expressed in heart tissue, we screened the coding sequences and corresponding intron flanks of the two genes and found two novel non-synonymous mutations in the MYPN gene and only one rare synonymous SNP in the coding region of the ANKRD1 gene.…”

“…3 The p.R1088H mutation reported in a case of familial DCM is located only one residue, amino-terminally, in the homologous fourth immunoglobulin-like domain as aligned to the corresponding position in the third domain, in which we detected our point mutation p.P961L. 31 Duboscq-Bidot et al 3 have shown that the p.R1088H mutation resulted in a decreased localization of myopalladin to the Z-band area of the left-ventricular cardiac myofibrils, similar to that which we found in the heart tissue from the p.P961L mutation carrier.…”

“…Epidemiological studies addressing the prevalence of gene mutations in DCM patients have demonstrated that inherited forms account for at least one-third of all DCM cases. [1][2][3][4] Familial cases frequently show a monogenic origin, and transmission indicates autosomal dominant or X-linked inheritance pattern with incomplete and age-dependent penetrance. 3 To date, positional cloning and candidate gene screening have led to the identification of numerous heterozygous mutations in more than 40 different genes, most of which encode proteins important for the structural integrity and function of cardiomyocytes, such as regulatory proteins of the sarcomere, the nuclear envelope or intracellular homeostasis.…”

“…[1][2][3][4] Familial cases frequently show a monogenic origin, and transmission indicates autosomal dominant or X-linked inheritance pattern with incomplete and age-dependent penetrance. 3 To date, positional cloning and candidate gene screening have led to the identification of numerous heterozygous mutations in more than 40 different genes, most of which encode proteins important for the structural integrity and function of cardiomyocytes, such as regulatory proteins of the sarcomere, the nuclear envelope or intracellular homeostasis. 1,2,5 In particular, defects in proteins required for force transduction and force transmission of the sarcomeric apparatus seem to promote the development of DCM.…”

“…11 Recently, mutations in the myopalladin-encoding MYPN and the CARP-encoding ANKRD1 gene (also termed ankyrin-repeat domain 1-encoded cardiac adriamycin responsive protein) have been reported in patients with DCM. 3,[12][13][14][15] As titin-binding proteins have been proposed to link mechanical load sensing in sarcomeres to myocardial gene expression, we extended the search for novel point mutations in a heterogeneous, but clinically well-characterized cohort of familial and sporadic DCM cases. Based on a mutational screening approach, we here present additional genetic variants identified in the two titinassociated proteins, which were thought to be most probably disease causing.…”