Abstract
Genome-wide mutagenesis was performed in mice to identify candidate genes for male infertility, for which the predominant causes remain idiopathic. Mice were mutagenized using N-ethyl-N-nitrosourea (ENU), bred, and screened for phenotypes associated with the male urogenital system. Fifteen heritable lines were isolated and chromosomal loci were assigned using low-density genome-wide SNP arrays. Ten of the 15 lines were pursued further using higher-resolution SNP analysis to narrow the candidate gene regions. Exon sequencing of candidate genes identified mutations in mice with cystic kidneys (Bicc1), cryptorchidism (Rxfp2), restricted germ cell deficiency (Plk4), and severe germ cell deficiency (Prdm9). In two other lines with severe hypogonadism, candidate sequencing failed to identify mutations, suggesting defects in genes with previously undocumented roles in gonadal function. These genomic intervals were sequenced in their entirety and a candidate mutation was identified in SnrpE in one of the two lines. The line harboring the SnrpE variant retains substantial spermatogenesis despite small testis size, an unusual phenotype. In addition to the reproductive defects, heritable phenotypes were observed in mice with ataxia (Myo5a), tremors (Pmp22), growth retardation (unknown gene), and hydrocephalus (unknown gene). These results demonstrate that the ENU screen is an effective tool for identifying potential causes of male infertility.
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Acknowledgments
This work was supported by NIH grants U01 HD043425 (JLJ) and U01 HD43430 (DRB); by the Northwestern University Genomics Core, which is supported by a Cancer Center Support Grant (NCI CA060553); and by the Northwestern University Biostatistics Collaboration Center, which is supported by a grant from the National Center for Research Resources (UL1 RR025741). The authors thank Timothy Barrett and Donna Emge for exceptional technical assistance.
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Weiss, J., Hurley, L.A., Harris, R.M. et al. ENU mutagenesis in mice identifies candidate genes for hypogonadism. Mamm Genome 23, 346–355 (2012). https://doi.org/10.1007/s00335-011-9388-5
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DOI: https://doi.org/10.1007/s00335-011-9388-5