| Total anomalous pulmonary venous return (TAPVR) is a congenital heart defect in which the pulmonary veins fail to connect to the left atrium returning instead to the right atrium or one of its venous tributaries. Using linkage analysis in a large family with autosomal dominant transmission of TAPVR, we mapped a TAPVR locus on chromosome 4pl3-q12. Linkage analysis in additional families and analysis of two overlapping founder-effect haplotypes limit the TAPVR-1 interval to proximal and distal intervals, each of about 1 cM. Further study of TAPVR has focused on physical mapping of the region, Fluorescence in situ hybridization (FISH) to search for chromosomal abnormalities, and screening of candidate genes.; As part of the search for candidate genes in the distal TAPVR-1 interval, I cloned and characterized a novel bicoid-related homeodomain-encoding gene named Sakasama (SAMA-1). Expression of SAMA-1 is tissue specific and developmentally regulated, with highest expression in the brain and lungs. Use of alternative transcription initiation sites, which may encode long and short forms of the protein, is also tissue specific and developmentally regulated. No mutations in this gene were discovered in any TAPVR patients. I have expressed this gene in Xenopus to test the hypothesis that it functions as an inhibitor of other bicoid-related homeodomain genes.; Other work toward my thesis focused on an X-linked recessive, neonatal lethal cardiomyopathy. called isolated noncompaction of the ventricular myocardium (INVM). We mapped this disorder to Xq28 using linkage analysis in a family with six affected males, four of whom died in the first year. The gene mapped near the Barth syndrome locus, which shares some phenotypic overlap, including cardiomyopathy. A glycine-to-arginine mutation was discovered in a conserved domain of the same protein defective in Barth syndrome, called Tafazzin. The INVM phenotype is more severe than most cases of the allelic Barth syndrome, which may be explained by the genotypes seen in each disorder. Efforts to elucidate the cellular function of Tafazzin by disruption of the yeast homologue, YPR140W have been initiated. Recent reports suggest the protein may function as an acyltransferase. |
