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An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y

Nature Genetics volume 23, pages 429–432 (1999)Cite this article

Abstract

In 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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Figure 1: AZFa region of the human Y chromosome.
Figure 2: De novo deletion at USP9Y splice-donor site in azoospermic man WHT2780.
Figure 3: Testicular histologies associated with AZFa deletion and USP9Y point mutation.

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Acknowledgements

We thank C. Tilford for developing several STSs used here; L. Brown for maintaining patient archives; E. Choi for screening BAC libraries; J. Jaruzelska for participation in variant screening; R. Alagappan, L. Pooler and M. Velez-Stringer for preparing genomic DNAs; M. Moore, D. Altshuler, B. Lahn, E. Lander and S. Rozen for support and advice; and R. Saxena and C. Tilford for comments on the manuscript. C.S. is the recipient of an NIH postdoctoral fellowship. This work was supported in part by NIH.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Whitehead Institute,

    Chao Sun, Helen Skaletsky, Zhaolan Tang & David C. Page

  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Chao Sun, Helen Skaletsky, Zhaolan Tang & David C. Page

  3. Whitehead Institute/MIT Center for Genome Research , Cambridge, Massachusetts, USA

    Bruce Birren & Keri Devon

  4. Infertility Center of St. Louis, St. Luke's Hospital , St. Louis, Missouri, USA

    Sherman Silber

  5. Department of Urology, Boston University School of Medicine, Boston, Massachusetts, USA

    Robert Oates

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Correspondence to David C. Page.

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Sun, C., Skaletsky, H., Birren, B. et al. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nat Genet 23, 429–432 (1999). https://doi.org/10.1038/70539

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