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Loss‐of‐function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype
Author(s) -
Maruthappu T.,
Posafalvi A.,
Castelletti S.,
Delaney P.J.,
Syrris P.,
O'Toole E.A.,
Green K.J.,
Elliott P.M.,
Lambiase P.D.,
Tinker A.,
McKenna W.J.,
Kelsell D.P.
Publication year - 2019
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.17388
Subject(s) - desmoplakin , palmoplantar keratoderma , frameshift mutation , nonsense mutation , loss function , phenotype , mutation , genetics , cardiomyopathy , biology , medicine , pathology , missense mutation , hyperkeratosis , gene , heart failure
Summary Background Arrhythmogenic cardiomyopathy ( AC ) is an inherited, frequently underdiagnosed disorder, which can predispose individuals 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 to be cardiac specific. Causative mutations frequently occur in desmosomal genes including desmoplakin ( DSP ). Objectives In this study, we systematically investigated the presence of a skin and hair phenotype in heterozygous DSP mutation carriers with AC . Methods Six 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. Results All carriers with mutations affecting both major DSP isoforms ( DSPI 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 DSPI . A mild palmoplantar keratoderma was also present in many carriers. Sanger sequencing of cDNA from nonlesional carrier skin suggested degradation of the mutant allele. Immunohistochemistry of patient skin demonstrated mislocalization of DSP and other junctional proteins (plakoglobin, connexin 43) in the basal epidermis. However, in Family 6, DSP localization was comparable with 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 among healthcare workers could facilitate a timely diagnosis of AC in the absence of overt cardiac features.