Mouse spermatogenesis-associated protein 1 (SPATA1), an IFT20 binding partner, is an acrosomal protein.

BACKGROUND: Intraflagellar transport is a motor-driven trafficking system that is required for the formation of cilia. Intraflagellar transport protein 20 (IFT20) is a master regulator for the control of spermatogenesis and male fertility in mice. However, the mechanism of how IFT20 regulates spermatogenesis is unknown. RESULTS: Spermatogenesis associated 1 (SPATA1) was identified to be a major potential binding partner of IFT20 by a yeast two-hybrid screening. The interaction between SPATA1 and IFT20 was examined by direct yeast two-hybrid, co-localization, and co-immunoprecipitation assays. SPATA1 is highly abundant in the mouse testis, and is also expressed in the heart and kidney. During the first wave of spermatogenesis, SPATA1 is detectable at postnatal day 24 and its expression is increased at day 30 and 35. Immunofluorescence staining of mouse testis sections and epididymal sperm demonstrated that SPATA1 is localized mainly in the acrosome of developing spermatids but not in epididymal sperm. IFT20 is also present in the acrosome area of round spermatids. In conditional Ift20 knockout mice, testicular expression level and acrosomal localization of SPATA1 are not changed. CONCLUSIONS: SPATA1 is an IFT20 binding protein and may provide a docking site for IFT20 complex binding to the acrosome area.

Murine germ cell-specific disruption of Ift172 causes defects in spermiogenesis and male fertility.

Intraflagellar transport (IFT) is a conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella. IFT172 is a component of the IFT complex. Global disruption of mouse Ift172 gene caused typical phenotypes of ciliopathy. Mouse Ift172 gene appears to translate two major proteins; the full-length protein is highly expressed in the tissues enriched in cilia and the smaller 130 kDa one is only abundant in the testis. In male germ cells, IFT172 is highly expressed in the manchette of elongating spermatids. A germ cell-specific Ift172 mutant mice were generated, and the mutant mice did not show gross abnormalities. There was no difference in testis/body weight between the control and mutant mice, but more than half of the adult homozygous mutant males were infertile and associated with abnormally developed germ cells in the spermiogenesis phase. The cauda epididymides in mutant mice contained less developed sperm that showed significantly reduced motility, and these sperm had multiple defects in ultrastructure and bent tails. In the mutant mice, testicular expression levels of some IFT components, including IFT20, IFT27, IFT74, IFT81 and IFT140, and a central apparatus protein SPAG16L were not changed. However, expression levels of ODF2, a component of the outer dense fiber, and AKAP4, a component of fibrous sheath, and two IFT components IFT25 and IFT57 were dramatically reduced. Our findings demonstrate that IFT172 is essential for normal male fertility and spermiogenesis in mice, probably by modulating specific IFT proteins and transporting/assembling unique accessory structural proteins into spermatozoa.

Association of MTHFR, NFKB1, NFKBIA, DAZL and CYP1A1 gene polymorphisms with risk of idiopathic male infertility in a Han Chinese population.

In this study, we investigated the association between six genetic polymorphisms (MTHFR C677T and A1298C, NFKB1 -94ins/del ATTG, NFKBIA 3'UTR A>G, DAZL A386G (T54A) and CYP1A1 T3801C) and the risk of idiopathic male infertility in a Chinese population. A case-control study comprising 1,759 idiopathic male infertile patients of Han Chinese ethnicity and 1,826 healthy fertile control individuals was carried out. Genotypes of all polymorphisms were determined via PCR-RFLP. Chi-squared test and logistic regression modeling were performed to identify the association of the polymorphisms with idiopathic male infertility. It was found that the heterozygous and variant genotypes of the following polymorphisms were significantly associated with an increased idiopathic male infertility risk: MTHFR C677T (heterozygous OR=1.266 [1.089, 1.470], P=0.002; variant OR=1.384 [1.138, 1.684], P=0.001), MTHFR A1298C (heterozygous OR=1.233 [1.071, 1.419], P=0.004; variant OR=1.564 [1.183, 2.068], P=0.002), and CYP1A1 T3801C (heterozygous OR=1.163 [1.007, 1.344], P=0.040; variant OR=1.232 [1.005, 1.510], P=0.045). When genotypes of non-significant polymorphisms were combined and analyzed, it was found that the combination between variant DD genotype of NFKB1 -94ins/del ATTG polymorphism and heterozygous AG genotype of DAZL A386G polymorphism was significantly associated with a reduced idiopathic male infertility risk (OR=0.588 [0.376, 0.919], P=0.02). In summary, we have successfully identified the association (or lack thereof) between the polymorphisms and idiopathic male infertility risk.