Nature Genetics
23, 429 - 432 (1999)
doi:10.1038/70539
An azoospermic man with a de novo point mutation in the Y-chromosomal
gene USP9YChao Sun1, Helen Skaletsky1, Bruce Birren2, Keri Devon2, Zhaolan Tang1, Sherman Silber3, Robert Oates4
& David C. Page11
Howard Hughes Medical Institute, Whitehead Institute,
and Department of Biology, Massachusetts Institute of Technology,
Cambridge, Massachusetts, USA. 2
Whitehead Institute/MIT Center for Genome Research
, Cambridge, Massachusetts, USA. 3
Infertility Center of St. Louis, St. Luke's Hospital
, St. Louis, Missouri, USA. 4
Department of Urology, Boston University School of
Medicine, Boston, Massachusetts, USA.
Correspondence should be addressed to David C. Page dcpage@wi.mit.eduIn humans, deletion of any one of three Y-chromosomal regions—AZFa, AZFb or AZFc—disrupts spermatogenesis, causing
infertility in otherwise healthy men1,
2,
3,
4,
5. Although
candidate genes have been identified in all three regions3,
6,
7,
8,
no case of spermatogenic failure has been traced to a point mutation in a
Y-linked gene, or to a deletion of a single Y-linked gene. We sequenced the AZFa region of the Y chromosome and identified two functional genes previously
described: USP9Y (also known as DFFRY) and DBY (refs 7,8). Screening 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 functional 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 truncation. This
mutation was present in a man with nonobstructive azoospermia (that is, no
sperm was detected in semen), but absent in his fertile brother, suggesting
that the USP9Y mutation caused spermatogenic failure. We also identified
a single-gene deletion associated with spermatogenic failure, again involving USP9Y, by re-analysing a published study.
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