title: ENU mutagenesis in mice identifies candidate genes for hypogonadism.
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.
authors.affiliation: Division of Endocrinology, Department of Medicine, Northwestern University Feinberg School of Medicine, 303 E. Superior Street, Chicago, IL 60611, USA. jeff-weiss@northwestern.edu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Weiss
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hurley
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Harris
authors.forename: Courtney
authors.initials: C
authors.lastname: Finlayson
authors.forename: Minghan
authors.initials: M
authors.lastname: Tong
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Fisher
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Moran
authors.forename: David R
authors.initials: DR
authors.lastname: Beier
authors.forename: Christopher
authors.initials: C
authors.lastname: Mason
authors.forename: J Larry
authors.initials: JL
authors.lastname: Jameson
mesh_terms: D000818:Animals; D005038:Ethylnitrosourea / Q000633:toxicity*; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D011506:Proteins / Q000235:genetics
chemical_list: D011506:Proteins; D005038:Ethylnitrosourea