An azoospermic man with a de novo point mutation in the Y-chromosomal geneUSP9Y

In humans, deletion of any one of three Y-chromosomal regions-AZFa. AZFb or AZFc-disrupts spermatogenesis, causing infertility in otherwise healthy me n(1-5). Although candidate genes have been identified in all three regions( 3,6-8), no case of spermatogenic failure has been traced to a point mutatio n in a Y-linked gene, or to a deletion of a single Y-linked gene. We sequen ced the AZFa region of the Y chromosome and identified two functional genes previously described: USP9Y(also known as DFFRY) and DBY (refs 7,8). Scree ning of the two genes in 576 infertile and 96 fertile men revealed several sequence variants, most of which appear to be heritable and of little funct ional consequence. We found one de novo mutation in USP9Y: a 4-bp deletion in a splice-donor site, causing an exon to be skipped and protein truncatio n. This mutation was present in a man with nonobstructive azoospermia (that is, no sperm was detected in semen), but absent in his fertile brother, su ggesting that the USP9Y mutation caused spermatogenic failure. We also iden tified a single-gene deletion associated with spermatogenic failure, again involving USP9Y, by re-analysing a published study.