Loss of function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype.

AIMS: Arrhythmogenic Cardiomyopathy (AC) is an inherited, frequently under diagnosed disorder, predisposing to sudden cardiac death. Rare, recessive forms of AC can be associated with woolly hair and palmoplantar keratoderma, but most autosomal dominant AC forms have been reported as cardiac specific. Causative mutations frequently occur in desmosomal genes including desmoplakin (DSP) In this study, we have systematically investigated the presence of a skin and hair phenotype in heterozygous desmoplakin (DSP) mutation carriers with AC.

METHODS AND RESULTS: 6 AC pedigrees with 38 carriers of a dominant loss of function (nonsense or frameshift) mutation in DSP were evaluated by detailed clinical examination (cardiac, hair and skin) and molecular phenotyping. All carriers with mutations affecting both major DSP isoforms (DSP I and II) were observed to have curly or wavy hair in the pedigrees examined except for members of Family 6, where the position of the mutation only affected the cardiac-specific isoform, DSP I. A mild palmoplantar keratoderma was also present in many carriers. Sanger sequencing of cDNA from non-lesional carrier skin suggested degradation of the mutant allele. Immunohistochemistry of patient skin demonstrated mislocalisation of DSP and other junctional proteins (plakoglobin, connexin 43) in the basal epidermis. However, in Family 6, DSP localisation was comparable to control skin.

CONCLUSIONS: This study identifies a highly recognizable cutaneous phenotype associated with dominant, loss of function DSPI/II mutations underlying AC. Increased awareness of this phenotype amongst healthcare workers could facilitate a timely diagnosis of AC in the absence of overt cardiac features. This article is protected by copyright. All rights reserved.