title: Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy.
abstract: BACKGROUND
  Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive myocardial atrophy with fibrofatty replacement. The recent identification of causative mutations in plakoglobin, desmoplakin (DSP), and plakophilin-2 (PKP2) genes led to the hypothesis that ARVC is due to desmosomal defects. Therefore, desmoglein-2 (DSG2), the only desmoglein isoform expressed in cardiac myocytes, was screened in subjects with ARVC.
  
  
  RESULTS
  In a series of 80 unrelated ARVC probands, 26 carried a mutation in DSP (16%), PKP2 (14%), and transforming growth factor-beta3 (2.5%) genes; the remaining 54 were screened for DSG2 mutations by denaturing high-performance liquid chromatography and direct sequencing. Nine heterozygous DSG2 mutations (5 missense, 2 insertion-deletions, 1 nonsense, and 1 splice site mutation) were detected in 8 probands (10%). All probands fulfilled task force criteria for ARVC. An endomyocardial biopsy was obtained in 5, showing extensive loss of myocytes with fibrofatty tissue replacement. In 3 patients, electron microscopy investigation was performed, showing intercalated disc paleness, decreased desmosome number, and intercellular gap widening.
  
  
  CONCLUSIONS
  This is the first investigation demonstrating DSG2 gene mutations in a significant number of ARVC-unrelated probands. Cardiac phenotype is characterized clinically by typical ARVC features with frequent left ventricular involvement and morphologically by fibrofatty myocardial replacement and desmosomal remodeling. The presence of mutations in desmosomal encoding genes in 40% of cases confirms that many forms of ARVC are due to alterations in the desmosome complex.
authors.affiliation: Department of Biology, University of Padua Medical School, Padua, Italy.
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Pilichou
authors.forename: Andrea
authors.initials: A
authors.lastname: Nava
authors.forename: Cristina
authors.initials: C
authors.lastname: Basso
authors.forename: Giorgia
authors.initials: G
authors.lastname: Beffagna
authors.forename: Barbara
authors.initials: B
authors.lastname: Bauce
authors.forename: Alessandra
authors.initials: A
authors.lastname: Lorenzon
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Frigo
authors.forename: Andrea
authors.initials: A
authors.lastname: Vettori
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Valente
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Towbin
authors.forename: Gaetano
authors.initials: G
authors.lastname: Thiene
authors.forename: Gian Antonio
authors.initials: GA
authors.lastname: Danieli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rampazzo
mesh_terms: D000293:Adolescent; D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D001706:Biopsy; D002648:Child; D004252:DNA Mutational Analysis; D051301:Desmoglein 2 / Q000235:genetics*; D003896:Desmosomes / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D051191:Plakophilins / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D053781:Transforming Growth Factor beta2
chemical_list: C495314:DSG2 protein, human; D051301:Desmoglein 2; C495337:PKP2 protein, human; D051191:Plakophilins; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2