title: A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy.
abstract: Familial Dilated Cardiomyopathy (FDCM) is caused by mutations in genes encoding myocardial force transduction proteins. Desmoglein-2 (DSG2) and Desmocollin-2 (DSC2) provide cellular adhesion and force transduction by cell-to-cell anchorage. To test whether perturbations of DSG2 or DSC2 exhibit a pathogenic impact on DCM pathogenesis, we sequenced both genes in 73 patients with FDCM and assessed prevalence of missense variations in matched control cohorts. We detected two missense variations in DSG2 (V55M and V919G) which were absent in 360 control alleles. Surprisingly, both variants were previously reported in patients with arrhythmogenic right ventricular cardiomyopathy. Yet, in the present study only the DSG2-V55M variant showed segregation with DCM in a family pedigree. Subsequent, analysis of 538 patients with idiopathic DCM and 617 consecutive control individuals resulted in identification of thirteen DSG2-V55M carriers with DCM, whereas only three control subjects harbored the variant. DSG2 immunostaining revealed pale structures of the intercalated disc in myocardium of one unique homozygous DSG2-V55M carrier. Furthermore, myocardial desmosomal structures were significantly shortened when compared to DCM myocardium negative for DSG2-V55M. Thus, our study identified the DSG2-V55M polymorphism as a novel risk variant for DCM associated with shortened desmosomes of the cardiac intercalated disc.
authors.affiliation: Experimental and Clinical Research Center (ECRC), Max-Delbrück Center for Molecular Medicine, Berlin, Germany. maximilian.posch@charite.de
authors.forename: Maximilian G
authors.initials: MG
authors.lastname: Posch
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Posch
authors.forename: Christian
authors.initials: C
authors.lastname: Geier
authors.forename: Bettina
authors.initials: B
authors.lastname: Erdmann
authors.forename: Wolf
authors.initials: W
authors.lastname: Mueller
authors.forename: Anette
authors.initials: A
authors.lastname: Richter
authors.forename: Volker
authors.initials: V
authors.lastname: Ruppert
authors.forename: Sabine
authors.initials: S
authors.lastname: Pankuweit
authors.forename: Bernhard
authors.initials: B
authors.lastname: Maisch
authors.forename: Andreas
authors.initials: A
authors.lastname: Perrot
authors.forename: Jens
authors.initials: J
authors.lastname: Buttgereit
authors.forename: Rainer
authors.initials: R
authors.lastname: Dietz
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haverkamp
authors.forename: Cemil
authors.initials: C
authors.lastname: Ozcelik
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D051301:Desmoglein 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003896:Desmosomes / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D020022:Genetic Predisposition to Disease; D005858:Germany; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment
chemical_list: C495314:DSG2 protein, human; D051301:Desmoglein 2