Mutations Stop Sperm Production - Whitehead Institute for Biomedical Research - Brief Article

Applied Genetics News, Dec 19, 1999

Howard Hughes investigator David Page, of the Whitehead Institute for Biomedical Research Whitehead Institute for Biomedical Research (9 Cambridge Ctr., Cambridge, MA 02142-1479; Tel: 617/258-5000) at Massachusetts Institute of Technology, has found the first mutation on the Y chromosome that completely prevents sperm production and thus causes male infertility. The finding, described in the December issue of Nature Genetics, may eventually help in the design of male contraceptives and in treatments for infertile males.

About 20% of cases of male infertility can be traced either to the loss of a large chunk of the male Y chromosome, or to some other large chromosome abnormality, such as the presence of a second X chromosome in a male. Page wanted to see which gene within one of the large missing Y chromosome chunks was important.

One of the genes, named USP9Y, contained variant DNA sequences in the samples from 5 infertile males out of 576 tested. Four of the changes were harmless-they were also present in a fertile brother or father or caused no change in the final protein product from the gene. The change in one individual, however, was not present in the individual's fertile brother, even though the two brothers had inherited the same Y chromosome from their father. The affected brother does not produce any sperm, but he does produce a mixture of sperm-precursor cells.

Some seminiferous tubules in the testes function normally, while others do not function at all. "It's as if the lights are going out one by one," says Page. "It makes me wonder whether the key to many of the problems will go back to the germ stem cells-the original sperm progenitor cells-whose job it is to keep the tubules populated with sperm-producing cells." A better understanding of how mutation causes infertility could suggest how to create infertility at will. A drug that antagonizes a gene such as USP9Y has the potential to be a male contraceptive.