CLINICAL RESEARCH: ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA
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
Manuscript received October 29, 2002;
revised manuscript received January 6, 2003,
accepted February 13, 2003.
* Reprint requests and correspondence: Dr. Tova Chajek-Shaul, Department of Medicine, Hadassah University Hospital, Mount Scopus, P.O. Box 24035, Jerusalem 91240, Israel.
chajek{at}hadassah.org.il
OBJECTIVES: The goal of this study was to analyze the genetic disorder of a family with cardiomyopathy, skin disorder, and woolly hair.
BACKGROUND: Arrhythmogenic right ventricular dysplasia (ARVD) is a heart muscle disorder causing arrhythmia and sudden cardiac death. We report a patient with familial autosomal recessive ARVD, woolly hair, and a pemphigous-like skin disorder with a new mutation in the desmoplakin gene.
METHODS: Genomic deoxyribonucleic acid was extracted from the patient’s blood and 12 first- and second-degree family members, and was amplified by polymerase chain reaction. Linkage analysis with polymorphic microsatellites was performed for 11 genes that code for structural desmosomal proteins. The genetic locus of the disease in this family was mapped to the chromosomal region 6p24 that contains the desmoplakin gene. Exons of the desmoplakin gene were analyzed by single-strand conformational polymorphism and direct sequencing. Confirmation of the mutation was carried out by restriction enzyme analysis.
RESULTS: We identified in the patient a homozygous missense mutation in exon 24 of the desmoplakin gene, leading to a Gly2375Arg substitution in the C-terminal of the protein where the binding site to intermediate filaments is located. Eight of 12 family members without hair or skin abnormalities were heterozygous for this mutation. The remaining 4, as well as 90 unrelated healthy control individuals of the same ethnic origin, were homozygous for the normal allele.
CONCLUSIONS: We have described a new mutation in the desmoplakin gene that causes familial ARVD. These findings suggest that desmosomal proteins play an important role in the integrity and function of the myocardium. Dysfunction of these proteins can lead to the development of cardiomyopathies and arrhythmias.
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Abbreviations and Acronyms
| | ARVD | | arrhythmogenic right ventricular dysplasia | | CT | | computed tomography | | DNA | | deoxyribonucleic acid | | ECG | | electrocardiogram | | ESC/ISFC | | European Society of Cardiology/International Society and Federation of Cardiology | | ICD | | implantable cardiac defibrillator | | IF | | intermediate filament | | PCR | | polymerase chain reaction | | PRD | | plakin repeat domain | | SSCP | | single-strand conformational polymorphism | | VT | | ventricular tachycardia |
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