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A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair

Ronny Alcalai, MD^*, Shulamit Metzger, PhD^*, Shimon Rosenheck, MD^*, Vardiella Meiner, MD and Tova Chajek-Shaul, MD^*,*

^* Department of Medicine Mount Scopus, Jerusalem, Israel
Department of Human Genetics, Hadassah University Hospital, Jerusalem, Israel

View larger version (142K): [in a new window]   Figure 1 Histological section (H & E x 40) of skin biopsy taken from the deceased patient’s brother. The histology is compatible with the diagnosis of pemphigus foliaceous.

View larger version (118K): [in a new window]   Figure 2 The 12-lead electrocardiogram (ECG) showing the difference between the right leads (V1 to V2) and the left leads (V5 to V6). (A) The ECG. (B) Detail of V2 and V6 demonstrating a 70-ms wider right-sided QRS compared with the left-sided one. (C) An ECG record of the patient during ventricular tachycardia (VT). The VT is left bundle branch block QRS configuration with 250-ms cycle length, originating in the right ventricular midseptal area.

View larger version (18K): [in a new window]   Figure 3 Pedigree of the family studied is characterized by high rates of consanguinity. Circles = females; diagonal lines = deceased; filled = living affected females; filled with broken line = family members who died suddenly and had skin and hair abnormalities; squares = male.

View larger version (29K): [in a new window]   Figure 4 (A) The G2375R mutation in the desmoplakin gene (bold) is a g to c substitution. (B) The protein sequence alignment of the mutated region in the human desmoplakin (HS DSP), in desmoplakin of other species (Mus musculus, Rattus norvegicus and Cricetulus griseus) and in other human plakin family members (PLE = plectin, EPP = epiplakin, BPA = bullos pemphigoid antigen1). The glycin in position 2375 of the human desmoplakin (bold) is extremely conserved.

View larger version (57K): [in a new window]   Figure 5 Gel electrophoresis of the mutation containing polymerase chain reaction product after digestion with Sma1. The mutant fragment is cleaved to two smaller fragments in similar size demonstrated by a single band, 365/357 base pairs (bp). The wild-type fragment is resistant to digestion and demonstrated by the higher single band, 722 bp.

View larger version (13K): [in a new window]   Figure 6 Domain structure of desmoplakin and the known mutation. The S229R mutation causes arrhythmogenic right ventricular dysplasia (17); the Q331X, Q664X, and C809X are nonsense desmoplakin mutations leading to functionally null alleles and cause striate palmoplantar keratoderma in heterozygotes (28–30). The G2375R and the 7901delG cause cardiomyopathy with skin and hair abnormalities.