Date of Award

Spring 2011

Author's School

College of Arts & Sciences

Author's Department/Program



Nkx2-5 is a cardiac transcription factor that plays a major role in embryonic heart development. Heterozygous Nkx2-5 knockout mice have an increased risk of heart malformation; ventricular septal defects (VSD, ~38.3% incidence) and atrial septal defects (ASD, ~40.2% incidence) occur most frequently. Crossing Nkx2-5+/- mice in one particular inbred strain, C57Bl/6, to others, i.e., FVB/N or A/J, has led to the discovery that polymorphisms of modifier genes influence the incidence and types of defects that result from Nkx2-5 mutation. In this study, we mapped atrial septal defect modifier genes onto a chromosomal location by genetic linkage analysis in an effort to discover genetic loci that influence risk and severity of ASD in the presence of an Nkx2-5 mutation. Binary linkage analysis of C57Bl/6 x FVB/n (n=162 affected) and C57Bl/6 x A/J (n=118 affected) F2 intercross mice revealed multiple strain-specific ASD susceptibility alleles located on different chromosomes. The LOD score for a C57Bl/6 x FVB/n chromosome 5 peak is indicative of an ASD-specific QTL with a strong effect at that particular locus. Capitalizing on variation in ASD size, continuous linkage analysis was performed to elucidate genes related to defect severity. The difference in LOD scores between the continuous and binary linkage analysis suggests that large ASDs are genetically distinct from small ASDs. One particular modifier locus discovered in the C57Bl/6 x A/J binary linkage analysis had been previously discovered to be correlated with VSD risk, and multiple loci appear to contribute to the development of both ASDs and VSDs in the presence of an Nkx2-5 mutation.


English (en)

Advisor/Committee Chair

Jay Lab

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