title: Screening of genes encoding junctional candidates in arrhythmogenic right ventricular cardiomyopathy/dysplasia.
abstract: OBJECTIVE
  Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy characterized by fibro-fatty replacement of the right ventricle and ventricular arrhythmias. The major disease-causing genes encode cardiac desmosomal components but are involved in only ∼50% of patients. To identify the missing genetic determinants, we used a candidate gene approach, focusing on the 3'-untranslated region (UTR) of the main ARVC/D gene PKP2 and on additional genes involved in desmosomal structure or function.
  
  
  RESULTS
  We screened a population of 64 ARVC/D probands with no identified mutations in any of the five known desmosomal genes (PKP2, DSG2, DSP, DSC2, and JUP). No putative mutation was identified in the 3'-UTR of PKP2 or in PNN, CTNNA3, CAV1, or PLN coding sequences. In a single proband, we identified two rare heterozygous missense variants affecting evolutionary conserved residues: c.175G>A (p.Gly59Arg) in PERP and c.1811A>G (p.Asp604Gly) in PKP4 (minor allele frequency <0.5% in control population).
  
  
  CONCLUSIONS
  Our study suggests that mutations in the candidate genes studied and regulation of PKP2 mRNA via 3'-UTR dependent mechanisms are unlikely to be major causes of ARVC/D in the studied population. Additional studies are needed to investigate the putative effects of rare PKP4 and PERP variants in this disease.
authors.affiliation: UPMC Univ Paris 6, INSERM, UMRS 956, AP-HP, 91 Boulevard de l'Hôpital, Paris F-75013, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Gandjbakhch
authors.forename: Alexia
authors.initials: A
authors.lastname: Vite
authors.forename: Françoise
authors.initials: F
authors.lastname: Gary
authors.forename: Véronique
authors.initials: V
authors.lastname: Fressart
authors.forename: Erwan
authors.initials: E
authors.lastname: Donal
authors.forename: Françoise
authors.initials: F
authors.lastname: Simon
authors.forename: Françoise
authors.initials: F
authors.lastname: Hidden-Lucet
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
authors.forename: Philippe
authors.initials: P
authors.lastname: Charron
authors.forename: Eric
authors.initials: E
authors.lastname: Villard
mesh_terms: D000595:Amino Acid Sequence; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D016147:Genes, Tumor Suppressor; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D006579:Heterozygote; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D051191:Plakophilins / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C416404:PERP protein, human; C105677:PKP4 protein, human; D051191:Plakophilins
keywords: Arrhythmogenic right ventricular cardiomyopathy/dysplasia; Candidate gene analysis; Cardiomyopathy; Desmosomes; Genetics; Mutation