MOLECULAR GENETIC BASIS FOR FAMILIAL ATRIAL FIBRILLATION

Masonic Medical Research Laboratory, Inc, Utica NY

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Abstract

DESCRIPTION (the applicant's description verbatim): The overall objective is to identify the gene responsible for familial atrial fibrillation (Afib) located at 10q22, map novel chromosomal loci, and attempt to identify one of the novel genes. Afib, the most common sustained dysrhythm, affects over two million Americans and accounts for one third of all strokes over the age of 65 years. Therapy ineffective in preventing or eliminating Afib is directed at controlling the heart rate and preventing systemic emboli. Financial burden is estimated at $9 billion annually. A molecular basis for Afib has yet to be determined. Accordingly, we identified five families of 83 members, including 36 affected, with Atib segregating as a highly penetrant autosomal dominant trait and mapped the chromosomal locus to 10q22. We have collected data and DNA on 20 additional families, four of which are not linked to 10q22 indicating genetic heterogeneity, and have identified another 100 probands with familial atrial fibrillation but no data has been collected. Initial region of 11.3 cM contained several candidate genes which were sequenced in the family and no mutation was identified. Subsequently, 2 additional families with recombinants narrowed the region to a genetic distance of 0.6 cM and physical distance of 1.2 mb. A continuous contig of the region was assembled with a six-BAC tiling path. There are 38 ESTs present in the region and 2 of the ESTs tested so far show cardiac expression one of which appears to be a zinc finger transcription factor. Aim I is to amplify and sequence both genes represented by these 2 cardiac ESTs in 2 normal and 2 affected family members. If no mutation is found (Aim II), genes represented by the remaining 36 ESTs known to be present in the region will be analyzed and those expressed in the heart will be sequenced in family members for mutations (as in Aim 1). Subsequently, if no mutations are identified, we (Aim 3) will attempt to identify sequences that code for unknown genes by methods such as analyzing additional BAG sequences using computerized homology searches against DNA, protein and EST databases and also using gene prediction software. After identification, these novel genes will be characterized and sequenced as in Aims 1 and 2. Concurrently, additional pedigrees segregating familial atrial fibrillation (Afib) will be collected and the phenotypes of affected individuals carefully characterized by clinical and electrocardiographic analysis. DNA isolated from individuals will be analyzed for known DNA markers and subjected to genetic linkage analysis to determine if the disease in any of these families is linked to the 10q22 locus and if so, the responsible mutations will be identified. We will also map novel chromosomal loci responsible for Afib in those families not linked to 10q22. For the novel locus with the smallest critical region, we will initially pursue the responsible gene by sequencing candidate genes located in the region and subsequently, if necessary, will pursue positional cloning as in Aims 1-3 to identify the responsible gene.