title: Homozygous founder mutation in desmocollin-2 (DSC2) causes arrhythmogenic cardiomyopathy in the Hutterite population.
abstract: BACKGROUND
  Dominant mutations in cellular junction proteins are the major cause of arrhythmogenic cardiomyopathy, whereas recessive mutations in those proteins cause cardiocutaneous syndromes such as Naxos and Carvajal syndrome. The Hutterites are distinct genetic isolates who settled in North America in 1874. Descended from <100 founders, they trace their origins to 16th-century Europe.
  
  
  RESULTS
  We clinically and genetically evaluated 2 large families of the Alberta Hutterite population with a history of sudden death and found several individuals with severe forms of biventricular cardiomyopathy characterized by mainly left-sided localized aneurysms, regions of wall thinning with segmental akinesis, in addition to typical electric and histological features known for arrhythmogenic right ventricular cardiomyopathy. We identified a homozygous truncation mutation, c.1660C>T (p.Q554X) in desmocollin-2 (DSC2), in affected individuals and determined a carrier frequency of this mutation of 9.4% (1 in 10.6) among 1535 Schmiedeleut Hutterites, suggesting a common founder in that subgroup. Immunohistochemistry of endomyocardial biopsy samples revealed altered expression of the truncated DSC2 protein at the intercalated discs but only minor changes in immunoreactivity of other desmosomal proteins. Recombinant expressed mutant DSC2 protein in cells confirmed a stable, partially processed truncated protein with cytoplasmic and membrane localization.
  
  
  CONCLUSIONS
  A homozygous truncation mutation in DSC2 leads to a cardiac-restricted phenotype of an early onset biventricular arrhythmogenic cardiomyopathy. The truncated protein remains partially stable and localized at the intercalated discs. These data suggest that the processed DSC2 protein plays a role in maintaining desmosome integrity and function.
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada. bgerull@ucalgary.ca
authors.forename: Brenda
authors.initials: B
authors.lastname: Gerull
authors.forename: Florian
authors.initials: F
authors.lastname: Kirchner
authors.forename: Jessica X
authors.initials: JX
authors.lastname: Chong
authors.forename: Julia
authors.initials: J
authors.lastname: Tagoe
authors.forename: Kumaran
authors.initials: K
authors.lastname: Chandrasekharan
authors.forename: Oliver
authors.initials: O
authors.lastname: Strohm
authors.forename: Darrel
authors.initials: D
authors.lastname: Waggoner
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Duff
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000473:pathology; D002648:Child; D051187:Desmocollins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004699:Endocardium / Q000473:pathology; D005260:Female; D015870:Gene Expression; D005838:Genotype; D005858:Germany; D057809:HEK293 Cells; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009656:North America; D010375:Pedigree; D010641:Phenotype; D055550:Protein Stability; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: C081561:DSC2 protein, human; D051187:Desmocollins; D011994:Recombinant Proteins
keywords: arrhythmogenic right ventricular cardiomyopathy; desmocollin-2; desmosomes; founder population; genetics; homozygous mutation; humans; sudden cardiac death or sudden death