Male infertility is a very common condition, with reports suggesting that one in 15-20 men of reproductive age are affected. Understanding why or how men produce defective sperm is a question that has remained elusive. We have used a combination of proteomic and genomic screens to identify both those proteins and genes responsible for building defective sperm in men. Interestingly, about 40 proteins are commonly dis-regulated within infertile sperm. Significantly, we have found that many of these proteins show atypical alternate splicing patterns. One such mechanism that explains this was the observation that several alternate-splicing regulators were up-regulated within defective sperm. As such, in proof of concept, we replicated this condition using transgenic flys. Our data show that sperm overexpression RNA-splicing regulators showed typical patterns of “male-factor” infertility, including (i) decreased amounts of sperm production, (ii) head morphology defects and (iii) poor sperm motility.
We have now extended these studies to identify genes that are mutated within defective sperm. Two single-nucleotide polymorphisms will be presented as candidates that explain cases of human male-factor infertility