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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.

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