Contrasting effects of Deadend1 (Dnd1) gain and loss of function mutations on allelic inheritance, testicular cancer, and intestinal polyposis

BACKGROUND: Certain mutations in the Deadend1 (Dnd1) gene are the most potent modifiers of testicular germ cell tumor (TGCT) susceptibility in mice and rats. In the 129 family of mice, the Dnd1(Ter) mutation significantly increases occurrence of TGCT-affected males. To test the hypothesis that he Dnd1(Ter) allele is a loss-of-function mutation; we characterized the consequences of a genetically-engineered loss-of-function mutation in mice, and compared these results with those for Dnd1(Ter). RESULTS: We found that intercrossing Dnd1(+/KO) heterozygotes to generate a complete loss-of-function led to absence of Dnd1(KO/KO) homozygotes and significantly reduced numbers of Dnd1(+/KO) heterozygotes. Further crosses showed that Dnd1(Ter) partially rescues loss of Dnd1(KO) mice. We also found that loss of a single copy of Dnd1 in Dnd1(KO/+) heterozygotes did not affect baseline occurrence of TGCT-affected males and that Dnd1(Ter) increased TGCT risk regardless whether the alternative allele was loss-of-function (Dnd1(KO)) or wild-type (Dnd1(+)). Finally, we found that the action of Dnd1(Ter) was not limited to testicular cancer, but also significantly increased polyp number and burden in the Apc(+/Min) model of intestinal polyposis. CONCLUSION: These results show that Dnd1 is essential for normal allelic inheritance and that Dnd1(Ter) has a novel combination of functions that significantly increase risk for both testicular and intestinal cancer.