Zebrafish as a model of variability in HDR syndrome

Most human birth defects are highly variable, yet we understand little about what generates this variability. In human, GATA3 mutation causes a highly variable disease, HDR (Hypoparathyroidism, sensorineural Deafness and Renal dysplasia) syndrome. Affected individuals can display any combination of the diagnostic HDR triad and can also have variable defects of the palatal skeleton. We have recovered a gata3 zebrafish mutant that exhibits “parathyroid”, sensorineural, kidney and palate defects. At least the defects to the palatal skeleton are highly variable. In two different genetic backgrounds the posterior palate is either completely lost or the palate is almost wild‐type in appearance. To determine how genetic background may ameliorate disease severity we performed microarray analyses for genes differentially regulated across genetic background in gata3 mutants. We found 45 genes that significantly interact between genotype and genetic background. We are currently performing loss‐ and gain‐of‐function analyses of these differentially expressed genes. Preliminary results show that at least some of these genes do alter the severity of the gata3 mutant phenotype in different genetic backgrounds.