Endeavors magazine: A suspect gene for faulty sperm

A suspect gene for faulty sperm

by Prashant Nair

Above: Microscopic images of sperm development show the presence of the JHDM2A protein (stained brown). The protein appears in the nucleus of round spermatids. No JHDM2A is detected in spermatozoa (last image on right).

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One faulty gene may cause infertility in some men, says Carolina researcher Yi Zhang. When Zhang deleted a gene in laboratory mice that helps package DNA into the heads of maturing sperm, he found that the mice produced immature sperm with little chance of successfully penetrating an egg.

Sperm cells’ multistage maturation process turns a tiny blob of genetic material into a sex cell with a whip-like tail that propels it forward on its path to the egg and a compact head that penetrates the egg.

Genes in the immature sperm head produce proteins that help the sperm mature. Proteins in the sperm head called histones hug the DNA and wrap it around themselves. When the time is right, the enzyme JHDM2A removes methyl groups from the histones. Then the histones release the DNA, allowing sperm to make another set of proteins, called protamines, which package the DNA in the sperm head tightly enough for penetration, Zhang says. Because the histones mask the genes until their methyl groups are removed, scientists call this process “silencing by methylation.”

Zhang created mice that lacked the enzyme JHDM2A. He found that the mutant mice had smaller testes than normal mice. “We found almost no mature sperm in the testes of the mutants,” Zhang says.

Although the mutation didn’t prevent the mice from having sex, they were infertile. Normal mouse sperm have hook-like heads. The sperm of the mutated mice had round heads and were mostly immotile. Deleting the JHDM2A enzyme affected packaging in the sperm head because the sperm could not produce protamines, Zhang adds.

Many other gene defects cause infertility in mice, but most of those genes have turned out to be normal in infertile men. Zhang says JHDM2A is another potential candidate, and infertility may be caused by a single-gene defect in at least some men.

Haifan Lin, director of the Yale Stem Cell Center, says Zhang’s work “represents a landmark contribution to reproductive biology.” Lin adds that although scientists have long known the role of protamines in sperm maturation, Zhang identified the enzyme that instructs genes to produce protamines.

Zhang is now collaborating with infertility researchers to study the enzyme in humans. “I’m almost certain that if there’s a mutation in this gene, it will cause male infertility,” he says.

Prashant Nair is a master’s student in medical journalism at Carolina.

Yi Zhang is a professor in the Department of Biochemistry and Biophysics, and a member of UNC’s Lineberger Comprehensive Cancer Center. His study was published in the November 1, 2007 issue of Nature.