1. ¹Centre for Cutaneous Research, Institute of Cell and Molecular Science, Queen Mary, University of London, Whitechapel, London, UK
2. ²Department of Dermatology, Royal Cornwall Hospital, Truro, UK
3. ³Department of Dermatology, South Glasgow University Hospitals, Glasgow, UK

Correspondence: David P. Kelsell, E-mail: d.p.kelsell@qmul.ac.uk

TO THE EDITOR

Desmosomes are major cell adhesion junctions, particularly abundant in the epidermis and the heart where absolute strength and rigidity of the tissue during mechanical stress is of vital importance. Desmoplakin (Dp) is the most abundant protein of the desmosome. We have previously shown that the Dp mutation 7901delG, which causes a frameshift and subsequent truncation of the protein with partial loss of the keratin-binding domain, has been found to be the underlying cause of an autosomal recessive syndrome presenting as dilated left ventricular cardiomyopathy, woolly hair, and striate palmoplantar keratoderma (Norgett et al., 2000). Subsequently, other Dp mutations have been described associated with cardiac and cutaneous syndromes (Alcalai et al., 2003; Uzumcu et al., 2006). Other Dp mutations have been reported associated either with non-syndromic striate palmoplantar keratoderma (Armstrong et al., 1999; Whittock et al., 1999) or with non-syndromic arrthymogenic right ventricular cardiomyopathy (Rampazzo et al., 2002). Here, we describe the identification of a novel dominant Dp mutation associated with striate palmoplantar keratoderma, woolly hair, and cardiomyopathy.

The patient first presented aged 3 years with hyperkeratosis and fissuring of the skin on her palms and soles (Figure 1). The hyperkeratosis on her feet extended over the Achilles tendon and she was also noted to have woolly unmanageable hair. Of note, her father apparently had a similar phenotype and died suddenly a month after her birth from arrthymogenic right ventricular dysplasia. No other known family members were affected. On examination at age 14, she had psoriasiform hyperkeratosis of the knees, elbows, and shins with prominence around hair follicles. She had a striate keratoderma of the palms and a focal keratoderma of the soles of her feet, which spread over the Achilles tendon. Her hair was noted to be kinky and woolly with short sparse hairs in the frontal scalp. She had absent molars and pre-molars, but normal nails and normal hearing. In view of her father's sudden death, she was referred for a cardiology opinion. Baseline investigations confirmed the original electrocardiogram and echocardiogram abnormalities. Cardiac magnetic resonance imaging confirmed the possibility of right ventricular dysplasia, although a more detailed echo suggested a bi-ventricular cardiomyopathy. Twenty-four-hour electrocardiogram monitoring demonstrated non-sustained ventricular tachycardia and, in view of her father's sudden death, a decision was made to implant a cardiac defibrillator. Repeat echocardiogram confirmed progression of her left ventricular dilatation with severe global impairment of systolic function. She died at age 18 years owing to a persistent dysrhythmia despite successful activation of the defibrillator.

Figure 1.

Skin and hair phenotypes of patient. Clinical pictures showing the striated keratoderma on (a) palm and (b) sole of the patient and (c, d) the woolly hair phenotype. 

Full figure and legend (182K)

After obtaining ethical approval with informed consent, venous blood and a 5 mm punch biopsy from palm skin were taken from the affected patient. All clinical investigation was conducted according to the Declaration of Helsinki Principles. No material was available from the deceased affected father. Genomic DNA was extracted using the Nucleon BACC3 kit (Nucleon Biosciences, Cambridge, UK) according to the manufacturer's instructions. The Dp gene was PCR amplified using conditions described previously (Whittock et al., 1999). PCR products were purified using the QIAquick PCR purification kit (QIAgen, Crawley, UK) according to the manufacturer's instructions and purified products were directly sequenced using ABI BigDye™ Terminator Cycle Sequencing Ready Reaction; precipitated products were loaded onto an ABI/PE Biosystems 377 automated sequencer (ABI/E, Warrington, UK) and sequence was analyzed using Sequence Navigator software v1.0.1.

A number of sequence variants were detected in the DNA from the patient and are summarized in Table S1. The majority were either synonymous, known polymorphisms, and/or were detected in normal control individuals. However, the heterozygous 30 bp insertion within exon 14 was likely to be disruptive (Figure 2). This was not found in the unaffected mother of this patient or in 160 control chromosomes by dHPLC (Transgenomic WAVE) analysis. The insertion occurs between the second and third nucleotides of codon 608 (isoleucine) resulting in the insertion of ten amino-acid residues (QSQFTDARKI). This variant represents the first reported insertion in the Dp gene.

Figure 2.

Heterozygous 30 bp insertion identified in exon 14 of the desmoplakin gene of the patient. (a) Genomic sequence of exon 14 in the patient showing the downstream effect of the 30 bp insertion on sequence quality. (b) Sequencing of subcloned exon 14 showing the three boxed nucleotides ATA code for the amino acid isoleucine (I608) on the wild-type allele of the patient, with the 30 bp insertion on the mutant allele occurring within this codon. Amino-acid sequence of the wild-type allele (c) and mutant allele (d) with insertion shown in grey. (e) WAVE traces obtained for exon 14 of the desmoplakin gene in the patient (i) compared to wild-type control (ii). This trace was not seen in 80 unrelated controls or in the unaffected mother of the patient.

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Immunofluorescence was carried out on a skin biopsy taken from this patient using antibodies against Dp, plakoglobin, and keratin 1 (Figure S1). In normal control skin, Dp and plakoglobin are both localized throughout the suprabasal layers of the skin and show a continuous band of staining, which circumvents the cell at the membrane. However, in the patient's skin, especially in the lower layers, the distribution of these proteins is not continuous around the cell membrane with some cytoplasmic localization. The localization of keratin 1 in patient skin was comparable to normal skin, suggesting that there is little effect on keratin 1–desmosomal interaction.

This heterozygous mutation results in the insertion of 10 amino-acid residues in the N-terminus of Dp and may effect sufficient recruitment of Dp into desmosomes and/or have a dominant-negative effect of the mutant on the recruitment of other desmosomal proteins. The latter is a possibility, as Dp has been shown to bind plakoglobin and plakophilins via its N-terminal head domain (Kowalczyk et al., 1997, 1999). However, this mutation lies just outside this critical binding domain but it may induce a conformational change that could effect Dp interactions with other desmosomal proteins. Therefore, it is tempting to speculate that the phenotype of this patient may be due to disruption of the interaction between Dp and other proteins known to be important in cardiac biology such as plakoglobin and plakophilin 2 (Bierkamp et al., 1996; McKoy et al., 2000; Gerull et al., 2004; Grossmann et al., 2004). However, the actual mechanism of disease needs further molecular and cellular studies. In conclusion, the fatal outcome in two generations in this family should alert dermatologists to the need to investigate cardiac function in patients with striate keratoderma, as early diagnosis and intervention may improve outcome.