We have described the Brachyrrhine (Br) mouse mutant, which carries a semidominant mutation that results in renal hypoplasia and frontonasal dysplasia. The homozygous mutation (Br/Br) is embryonic lethal and the heterozygote mutant (Br/+) survives to adulthood, but shows severe midfacial retrognathia and a greatly decreased nephron number. We have mapped the Br mutation to a 171 kb critical region on chromosome 17 which contains only one gene, the homeobox transcription factor six2. Although extensive sequencing of the six2 gene failed to identify the Br mutation, expression analysis showed a 50% decrease in six2 in the midface and kidney of Br/+ mice, and an almost complete absence of six2 in Br/Br mice. Our current hypothesis is that a distant cis‐acting regulatory region for six2 has been mutated in the Br mice, resulting in a silencing of the six2 gene during embryonic development. To determine if restored six2 expression can rescue the Br mutant phenotype, we generated transgenic mice using intracytoplasmic sperm injection with a 192 kb BAC spanning the Br critical region and containing a wild type copy of the six2 gene. With PCR and Southern Blotting we found that 17% of the pups born carried the BAC. Offspring were genotyped for the Br mutation using the D17Mit76 microsatellite, and current work is directed at determining the extent of phenotype rescue in Br mice. Supported by R01 DK064752 (SL) and P20 RR016467 (SM).