title: De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease.
abstract: OBJECTIVE
  Arrythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an autosomal-dominantly inherited disease caused by mutations in genes encoding desmosomal proteins and is characterised by fibrofatty replacement occurring predominantly in the right ventricle and can result in sudden cardiac death. Naxos and Carvajal syndrome, autosomal recessive forms of ARVC/D, are characterised by involvement of the right and/or left ventricle in association with palmoplantar keratoderma and woolly hair. The aim of the present study has been to screen for mutations in the desmosomal protein genes of two unrelated patients with Naxos-Carvajal syndrome.
  
  
  RESULTS
  Desmosomal protein genes were screened for mutations by polymerase chain reaction as well as direct sequencing approach. In each patient we identified a single heterozygous de novo mutation in the desmoplakin gene DSP, p.Leu583Pro and p.Thr564Ile, leading to severe combined cardiac/dermatological and cardiac/dermatological/dental phenotypes. The DSP missense mutations are localised in the N terminal domain of desmoplakin.
  
  
  CONCLUSIONS
  The identified variations in DSP involve highly conserved residues. Moreover, the variations are de novo mutations and they are localised in critical protein domains that appear to be mutation hot spots. We assume that these heterozygous variations are causal for the mixed Naxos-Carvajal syndrome phenotype in the screened patients.
authors.affiliation: Cardiology Department, University Hospital Zurich and University Hospital Balgrist, Zurich, Switzerland. dagmar.keller@balgrist.ch
authors.forename: Dagmar I
authors.initials: DI
authors.lastname: Keller
authors.forename: Dimitri
authors.initials: D
authors.lastname: Stepowski
authors.forename: Christian
authors.initials: C
authors.lastname: Balmer
authors.forename: Françoise
authors.initials: F
authors.lastname: Simon
authors.forename: Joelle
authors.initials: J
authors.lastname: Guenthard
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bauer
authors.forename: Peter
authors.initials: P
authors.lastname: Itin
authors.forename: Nadine
authors.initials: N
authors.lastname: David
authors.forename: Valérie
authors.initials: V
authors.lastname: Drouin-Garraud
authors.forename: Véronique
authors.initials: V
authors.lastname: Fressart
mesh_terms: D000293:Adolescent; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis / Q000235:genetics*; D051180:Desmoplakins / Q000235:genetics*; D005260:Female; D006201:Hair Diseases / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007645:Keratoderma, Palmoplantar / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense
chemical_list: D051180:Desmoplakins