title: Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy.
abstract: OBJECTIVE
  Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of juvenile sudden death and is characterized by fibro-fatty replacement of the right ventricle. Mutations in several genes encoding desmosomal proteins have been identified in ARVC. We speculated that αT-catenin, encoded by CTNNA3, might also carry mutations in ARVC patients. Alpha-T-catenin binds plakophilins and this binding contributes to the formation of the area composita, which strengthens cell-cell adhesion in contractile cardiomyocytes.
  
  
  RESULTS
  We used denaturing high-performance liquid chromatography and direct sequencing to screen CTNNA3 in 76 ARVC patients who did not carry any mutations in the desmosomal genes commonly mutated in ARVC. Mutations c.281T > A (p.V94D) and c.2293_2295delTTG (p.del765L) were identified in two probands. They are located in important domains of αT-catenin. Yeast two-hybrid and cell transfection studies showed that the interaction between the p.V94D mutant protein and β-catenin was affected, whereas the p.del765L mutant protein showed a much stronger dimerization potential and formed aggresomes in HEK293T cells.
  
  
  CONCLUSIONS
  These findings might point to a causal relationship between CTNNA3 mutations and ARVC. This first report on the involvement of an area composita gene in ARVC shows that the pathogenesis of this disease extends beyond desmosomes. Since the frequency of CTNNA3 mutations in ARVC patients is not rare, systematic screening for this gene should be considered to improve the clinical management of ARVC families.
authors.affiliation: Department for Molecular Biomedical Research,  VIB, Ghent University, Technologiepark 927, B-9052  Ghent,  Belgium.
authors.forename: Jolanda
authors.initials: J
authors.lastname: van Hengel
authors.forename: Martina
authors.initials: M
authors.lastname: Calore
authors.forename: Barbara
authors.initials: B
authors.lastname: Bauce
authors.forename: Emanuela
authors.initials: E
authors.lastname: Dazzo
authors.forename: Elisa
authors.initials: E
authors.lastname: Mazzotti
authors.forename: Marzia
authors.initials: M
authors.lastname: De Bortoli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Lorenzon
authors.forename: Ilena E A
authors.initials: IE
authors.lastname: Li Mura
authors.forename: Giorgia
authors.initials: G
authors.lastname: Beffagna
authors.forename: Ilaria
authors.initials: I
authors.lastname: Rigato
authors.forename: Mara
authors.initials: M
authors.lastname: Vleeschouwers
authors.forename: Koen
authors.initials: K
authors.lastname: Tyberghein
authors.forename: Paco
authors.initials: P
authors.lastname: Hulpiau
authors.forename: Evelien
authors.initials: E
authors.lastname: van Hamme
authors.forename: Tania
authors.initials: T
authors.lastname: Zaglia
authors.forename: Domenico
authors.initials: D
authors.lastname: Corrado
authors.forename: Cristina
authors.initials: C
authors.lastname: Basso
authors.forename: Gaetano
authors.initials: G
authors.lastname: Thiene
authors.forename: Luciano
authors.initials: L
authors.lastname: Daliento
authors.forename: Andrea
authors.initials: A
authors.lastname: Nava
authors.forename: Frans
authors.initials: F
authors.lastname: van Roy
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rampazzo
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004562:Electrocardiography; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D051178:alpha Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C441963:CTNNA3 protein, human; D051178:alpha Catenin