Elsevier

The Lancet

Volume 355, Issue 9221, 17 June 2000, Pages 2119-2124
The Lancet

Articles
Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease)

https://doi.org/10.1016/S0140-6736(00)02379-5Get rights and content

Summary

Background

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant heart muscle disorder that causes arrhythmia, heart failure, and sudden death. Previously we mapped the genetic locus for the triad of autosomal recessive ARVC, palmoplantar keratoderma, and woolly hair (Naxos disease) to chromosome 17q21, in which the gene for plakoglobin is encoded. This protein is a key component of desmosomes and adherens junctions, and is important for the tight adhesion of many cell types, including those in the heart and skin.

Methods

We studied 19 individuals with Naxos disease, as well as unaffected family members and unrelated individuals from the neighbouring Greek islands of Naxos and Milos. Gene sequence was determined by reverse transcriptase PCR from RNA isolated from the skin of an affected individual and mutations in other cases were confirmed by restriction-enzyme analysis.

Findings

A homozygous 2 base pair deletion in the plakoglobin gene was identified only in the 19 affected individuals. This deletion caused a frameshift and premature termination of the protein, which was shown by western blot analysis. 29 clinically unaffected family members were heterozygous for the mutation; 20 unrelated individuals from Naxos and 43 autosomal dominant ARVC probands were homozygous for the normal allele.

Interpretation

The finding of a deletion in plakoglobin in ARVC suggests that the proteins involved in cell-cell adhesion play an important part in maintaining myocyte integrity, and when junctions are disrupted, cell death, and fibrofatty replacement occur. Therefore, the discovery of a mutation in a protein with functions in maintaining cell junction integrity has important implications for other dominant forms of ARVC, related cardiomyopathies, and other cutaneous diseases.

Introduction

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart-muscle disorder characterised by the fibrofatty replacement of cardiomyocytes and extracellular matrix. Right ventricular features predominate, but left ventricular involvement can also arise with disease progression. The main clinical complications are arrhythmia, heart failure, and sudden death. There is also a higher than expected rate of structural, functional, and electrocardiographic abnormalities in family members of people with ARVC, which could represent early disease.1 The subtlety of the clinical phenotype often causes difficulties in establishment of a definitive diagnosis. The prevalence of inherited forms of ARVC has not been established by systematic clinical genetic studies, but at least 30% of the disease is familial, with autosomal dominant inheritance. Autosomal dominant forms of ARVC have been mapped to chromosomal loci at 14q232 1q42,3 14q12,4 2q32,5 and 3p23.6 No causative gene has yet been identified.

An autosomal recessive ARVC has also been reported. Protonotarios and colleagues7 examined the population of the Greek island of Naxos and described Naxos disease; a syndrome of ARVC, non-epidermolytic palmoplantar keratoderma (NEPPK), and woolly hair. The autosomal recessive ARVC of Naxos disease is similar to autosomal dominant ARVC with respect to age and mode of clinical presentation, distribution of right ventricular and left ventricular involvement, electrocardiographic features, natural history, and morphological and histological features (figure 1).8, 9 Initial clinical presentation is often with ventricular arrhythmia of left-bundle-branch-block morphology, which suggests a right ventricular origin. Detailed right ventricular imaging (magnetic resonance, two dimensional echo), however, might not be sensitive enough to show right ventricle wall thinning or aneurysmal outpouching, which typically involves the inflow, outflow, or apical regions, or all three. In the Naxos families, cosegregation of hair (present at birth) and skin features with cardiomyopathy presents a powerful model for gene identification in ARVC, since cardiac disease status could be confidently assigned on the basis of the ectodermal dysplasia.7, 9

We have previously confirmed autosomal recessive inheritance for Naxos disease and mapped the disorder to chromosome 17q21.10 We have refined the region of homozygosity delineating the disease locus to a 0·7 cM interval between the genetic markers D17S800 and D17S1789. This critical region contains the candidate gene plakoglobin,11 a member of the armadillo protein family and a constituent protein in adherens and desmosomal junctions, with adhesive and signalling functions.12 Mice with null mutations of plakoglobin exhibit heart and skin abnormalities analogous to Naxos disease.13, 14 We describe a deletion mutation in plakoglobin (Pk2157del2) that cosegregates with this disease.

Section snippets

Patients and clinical material

Patients with Naxos disease and clinically unaffected family members were recruited from the Greek islands of Naxos and Milos by use of the screening criteria described previously.1, 10 Briefly, cardiac involvement typical of ARVC was ascertained by non-invasive cardiac assessment in all, and by examination of cardiac histology in five. The skin abnormality was identified by the presence of non-epidermolytic palmoplantar keratoderma from infancy, and the hair abnormality was characterised by

Results

Screening of the plakoglobin cDNA from a patient with Naxos disease identified a 2 base pair (TG) deletion at the 3′ end of the gene. Sequence analysis of the corresponding genomic region in Naxos patients and non-Naxos controls, shows that the deletion is 7 base pairs from a 3′ splice junction (figure 2). The deletion of nucleotides 2157 and 2158 (Pk2157del2) causes a frameshift and premature termination of translation (figure 3A). This frameshift alters the last five aminoacid residues in the

Discussion

We have shown a 2 base pair homozygous deletion in the plakoglobin gene in individuals with Naxos disease. Plakoglobin is an important component of the cell-cell and cell-adhesion complex of many tissues, including the cytoplasmic plaque of cardiac junctions16 and the dermal-epidermal junctions of the epidermis.17 Plakoglobin has a potential signalling role in the formation of desmosomal juctions, and is thought to serve as a linker molecule between the inner and outer portions of the

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