ENU mutagenesis in mice identifies candidate genes for hypogonadism

Jeffrey Weiss*, Lisa A. Hurley, Rebecca M. Harris, Courtney Finlayson, Minghan Tong, Lisa A. Fisher, Jennifer L. Moran, David R. Beier, Christopher Mason, J. Larry Jameson

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)346-355
Number of pages10
JournalMammalian Genome
Volume23
Issue number5-6
DOIs
StatePublished - Jun 1 2012

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ASJC Scopus subject areas

  • Genetics

Cite this

Weiss, J., Hurley, L. A., Harris, R. M., Finlayson, C., Tong, M., Fisher, L. A., Moran, J. L., Beier, D. R., Mason, C., & Jameson, J. L. (2012). ENU mutagenesis in mice identifies candidate genes for hypogonadism. Mammalian Genome, 23(5-6), 346-355. https://doi.org/10.1007/s00335-011-9388-5