Mutagenesis-generated mouse models of human infertility with abnormal sperm

Abstract

BACKGROUND: The aetiology of human male fertility, with impairment of sperm number, motility and morphology (oligoasthenoteratozoospermia), has been difficult to understand, partly for lack of animal models. METHODS: An ethylnitrosourea (ENU) mutagenesis strategy has been successful in producing heritable gene mutations with phenotypes similar to human male infertility, and here, we describe three independent ENU-induced mutations that cause a phenotype of oligoasthenoteratozoospermia in mice. RESULTS: The loci identified by these three mutations are designated swm2, repro2 and repro3. All mutant males were characterized by low sperm concentration, poor sperm morphology and negligible motility, but the infertile males were apparently normal in other respects. Sperm from mutant males failed to fertilize oocytes in vitro. Ultrastructural analyses revealed varied abnormalities apparent in both testicular spermatids and epididymal sperm. Genetic mapping placed the swm2 gene on chromosome 7, the repro2 gene on chromosome 5 and the repro3 gene on chromosome 10. CONCLUSION: The single-gene mutations caused complex and non-specific sperm pathologies, a point with important implications for managing cases of human male infertility. The ultimate identification of the loci for the mutations causing these phenotypes will clarify aetiology of complex syndromes of infertility with sperm abnormalities consistent with oligoasthenoteratozoospermia.

Gene trap mutation of murine Outer dense fiber protein-2 gene can result in sperm tail abnormalities in mice with high percentage chimaerism

“…This is in agreement with our earlier studies [7] that suggested that the axonemal doublet functions in part as anchor for the formation of the corresponding ODF: we demonstrated that Spag4 binds to the doublet followed by binding of Odf1 and other ODF proteins to Spag4. In a large mouse mutagenesis study [29] the Repro2 mutation was shown to result in elongated spermatids with an apparently normal axoneme, some aligned mitochondria and a disorganized array of ODF in the cytoplasm: these mice also suffer from dysplasia of the fibrous sheath [30]. Sperm tail abnormalities in humans have been classified in two groups [31-33]: a heterogeneous set of different sperm abnormalities as seen in low frequency in infertile men, and a specific set of sperm abnormalities seen in individuals.…”

Novel epididymal proteins as targets for the development of post-testicular male contraception

“…An opposite strategy applies to the phenotype-based gene discovery process. The N-ethyl-N-nitrosourea (ENU)-induced chemical mutagenesis strategy is one of the available methods to generate point mutations in male mouse (and to lesser extend female) germ cells (Kennedy et al 2005, Handel et al 2006, Lessard et al 2007. Mice harboring the mutations are bred to homozygosity and reproductive tests are performed to identify mutations that cause infertility.…”

Mouse models in male fertility research

“…[23][24][25][26][27][28] Knockout/knockin mice and gene-trapped mice The most common approach used to define a gene function in vivo is gene ablation by homologous recombination in embryonic stem (ES) cells, known as 'knockout' or 'gene targeting'. 29,30 This strategy is designed for the evaluation of a gene function on the basis of the complete elimination (null allele) or partially elimination of a candidate gene function (that is, deletion of particular domain(s) of the encoded protein).…”