Gene for Arrhythmogenic Right Ventricular Cardiomyopathy With Diffuse Nonepidermolytic Palmoplantar Keratoderma and Woolly Hair (Naxos Disease) Maps to 17q21

Abstract

Background —Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease of unknown etiology that causes arrhythmias, heart failure, and sudden death. Diagnosis can be difficult, and this hampers investigation of its molecular basis. Forms of ARVC in which gene penetrance and disease expression are greater should facilitate genetic study. We undertook a clinical and genetic investigation of Naxos disease, originally described by Protonotarios in 1986. This disease constitutes the triad of ARVC, diffuse nonepidermolytic palmoplantar keratoderma, and woolly hair. Methods and Results —We evaluated the population of Naxos, Greece, to identify probands, which was followed by family screening. Twenty-one affected persons from 9 families of 150 persons were identified. Linkage analysis was performed with microsatellite markers. The disease locus mapped to 17q21. A peak 2-point LOD score of 3.62 at θ=0.0 was found with a marker within intron 4 of the keratin 9 gene, a member of the type I (acidic) keratin family. A preserved homozygous disease haplotype was identified. Haplotype analysis delimited the disease interval. Conclusions —Hair and skin abnormalities were found to be reliable markers of subsequent heart disease. This suggests the presence of a single mutant gene with novel cardiac, skin, and hair function or two or more tightly linked disease genes. Recessive inheritance of Naxos disease and a founder effect were demonstrated. Identification of a fully informative genetic marker linked to the disease and uncommon in the background population may be of use as a test to identify disease gene carriers.

Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

“…Initial mapping of this disorder pointed to the chromosomal locus 17q21, 8 and candidate-gene sequencing within this region revealed a homozygous 2 bp deletion (c.2157-2158delGT) in the junction plakoglobin gene (JUP) that was present only in affected individuals (Figure 2A). 9 Subsequent studies showed that among subjects homozygous for this mutation, the disease is completely penetrant by adolescence.…”

Arrhythmogenic right ventricular cardiomyopathy: asymptomatic to life threatening as illustrated by the cases of two sisters

“…Several genetic loci have been reported to be associated with the disease and mutations in six genes have been identified: ryanodine receptor, plakoglobin, desmoplakin and recently transforming growth factor-β, plakophilin-2 and desmoglein. [9][10][11][12][13][14][15][16] Patients with mutations in the ryanodine receptor gene, also called ARVC2, are more prone to develop arrhythmias. 17 The recognition that ARVC is frequently familial and can cause arrhythmic death leads to the challenge to identify family members who are at risk.…”

Evaluation of Signal-Averaged Electrocardiography for Clinical Diagnosis in Arrhythmogenic Right Ventricular Dysplasia.

“…A familial predisposition for ARVD has been described, suggesting that a genetic factor may be involved. [1][2][3][4][5][6][8][9][10][11][12][13][14][15][16] Only 10% of patients are diagnosed before the age of 20, probably because the arrhythmia is not apparent during this stage of life. However, patients with ARVD have an increased risk of cardiac sudden death.…”

“…25) A screening test for detecting patients with ARVD is needed, since the SAECG procedure is neither complicated nor time consuming (about 10 minutes). 15) Moreover, it is cost-effective and only reguires 1 meter of recording paper. The reasons why we utilizede time domain method instead of frequency domain method to study the SAECG are as follows: 26,27) 1) Time domain method is well established and has good reproducibility, 2) Frequency domain method is well utilized.…”