Genetic Origin of Defects in Atrioventricular Conduction

Medical University Of South Carolina, Charleston SC

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Abstract

Previously, we identified heterozygote mutations in a transcription factor, CSX/NKX2.5, that result in atrioventricular (AV) conduction disturbance and a variety of congenital structural malformations of the heart. In more recent analyses of NKX2.5 mutations in humans, we have obtained data indicating that nonsense or missense mutations in the homeodomain are associated with the AV conduction disturbance phenotype, while missence mutations in the C- or N-terminus or NKX2.5 are not. In the studies outlined in this project, we have two objectives that build on these observations. First, we propose to identify other single gene defects associated with AV conduction abnormalities, focusing particularly on candidate genes known to influence embryonic pattern formation (e.g. NKX2.5). Second we will use targeted transgenesis in animal models to characterize the developmental pathogenesis of human NKX2.5 mutations already identified. Specific Aims 1 and 2 relate to the first goal. Here, developmental pathogenesis of human NKX2.5 mutations already identified. Specific Aims 1 and 2 relate to the first goal. Here, we will utilize genetic linkage analysis in kindreds in whom affected individuals have abnormal AV conduction. Mutation analysis of candidate genes in probands with idiopathic AV conduction disturbance will also be undertaken. Candidate genes will be identified by their chromosomal genetic locus and/or their significance to embryonic development of conduction system. In related to the second goal, it established that NKX2.5 is expressed during recruitment of mesodermal cells to early cardiogenic lineages; our preliminary evidence indicates that NKX2.5 is secondary up-regulated in differentiating conduction cells. Based on these data, we hypothesize that NKX2.5 functions in phenotype commitment during active recruitment of myocytes to the conduction system. In Specific Aim 3, our objective is to use an AV conduction specific promoter (cGATA-6) to express disease-associated NKX2.5 allels in transgenic mice. Our hypothesis is that specific NKX2.5 mutations will result in predictable levels of under recruitment to the central conduction system. In Specific Aim 4, we will use direct over-expression of NKX2.5 in heart to determine if up-regulation of wild type of mutant forms of NKX2.5 result in ectopic/increased levels of commitment by myocytes to conductive lineages. Elucidation of the genetic basis and genotype- phenotype relations of AV conduction disturbance will provide insight into pattern formation in developing heart and improve understanding of the molecular and genetic basis of human malformations.