| Summary: | Thesis (M.Sc.)--Memorial University of Newfoundland, 2009. Medicine Includes bibliographical references (leaves 75-87) Cardiomyopathy is a disease that affects the muscle of the heart. It has a variety of causes, symptoms, and treatments. As the disease progresses, the heart becomes weaker and less able to pump blood through the body. There are four major groups of cardiomyopathy, which include Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), Dilated Cardiomyopathy (DCM), Hypertrophic Cardiomyopathy (HCM), and Restrictive Cardiomyopathy (RCM). -- Mutations causing ARVC have been previously found in seven genes. Five of these (PKP2, DSP, DSC2, JUP, DSG2) code for desmosomal proteins and are functionally important for cell-to-cell adhesion. A sixth gene, RYR2, is a phenocopy involved in calcium release mechanisms. A seventh gene, TGFβ33, , is implicated in rare cases of ARVC. One of the twelve loci implicated in ARVC is designated Arrhythmogenic Right Ventricular Dysplasia Type 5 (ARVD5). Inheritance is in an autosomal-dominant pattern. It, like desmosomal ARVC, is characterized predominantly by the replacement of cardiomyocytes with fatty and fibrous tissue, which can increase the risk of sudden cardiac death (SCD). In 1998, linkage analysis and a genome wide scan, using a family from Newfoundland, identified an autosomal-dominant form of ARVC mapping to a 9.93 Mb region on chromosome 3p25. -- The primary objective of this study was to reduce the linked candidate region, by identifying recombinations and/or a consistent disease-associated haplotype in additional ARVD5-linked Newfoundland families. The secondary objective was to identify the disease-causing gene. -- Genomic DNA was collected from obligate carriers and affected members from 15 Newfoundland families and was used to construct high-resolution haplotypes. Fine mapping reduced the candidate region from 9.93 Mb to 2.36 Mb. A common haplotype co-segregated with the disease suggesting a common founder in these 14 Newfoundland families and a common mutation causing the disease. Direct sequencing of twenty positional candidate genes identified a novel missense mutation (c.1073 C→T, S358L), in the TMEM43 gene, which was carried by all ARVC patients and absent from 322 population control chromosomes. TMEM43 is a novel causative gene for ARVC at the ARVD5 locus. Presymptomatic diagnosis of at-risk individuals can be carried out due to this mutation discovery.
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