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P&S Journal

P&S Journal: Winter 1997, Vol.17, No.1
Research Reports
Gene Implicated in Heart Disease Linked to Male Infertility

A gene that helps control cholesterol levels may play a role in male infertility, according to a collaborative study by P&S and Mount Sinai School of Medicine researchers. The study, published in an October issue of Proceedings of the National Academy of Sciences, marks the first time a genetic factor affecting male fertility has been identified on a chromosome other than the Y chromosome. Up to 10 percent of the adult male population of the United States suffers from infertility.

Normally, the apoliprotein B (apo B) gene produces a major protein component of LDL cholesterol, which is associated with coronary heart disease, says Dr. Li-Shin Huang, assistant professor of medicine and co-author of the study. But when Dr. Huang tried to study the function of apo B in mice by inactivating the gene, she found that heterozygous male knockout mice--those with only one working copy of the gene--were infertile. (Homozygous mice, in which both copies of the gene were inactivated, died in early gestation.)

Dr. Huang then teamed up with Drs. Emanuel Voyiaziakis, staff associate in medicine at P&S; Jon W. Gordon and Hsiang Lih Chen of Mount Sinai; and Edward M. Rubin of Lawrence Berkeley Laboratory, to investigate further. The researchers found the heterozygous mice had functional abnormalities in their sperm, including a low sperm count, reduced motility, and shorter survival time. Furthermore, by using techniques related to in vitro fertilization, they found that sperm of the mice were not able to penetrate the zona pellucida (the elastic envelope that surrounds an ovum). Fertilization normally occurs when a single sperm penetrates the zona pellucida.

The researchers also discovered that apo B messenger RNA (mRNA) was expressed in the testis and epididymis of normal mice. Previously, scientists believed that apo B mRNA was expressed only in the liver and intestine of such mice. In addition, compared to mice with two normal copies of the apo B gene, the heterozygous mice had lower levels of apo B mRNA. "These findings imply that apo B may have a direct function in gonadal tissues," says Dr. Huang. She cautions that further studies are needed before a definitive connection can be made.

If the link between infertility and apo B holds up, it may have treatment implications for human infertility. "The abnormalities that we see in mice are much like idiopathic infertility in men," says Dr. Huang. "We know there are humans with defective apo B, but no formal studies have been done to determine if they have fertility problems. The next step will be to associate apo B levels with infertility."

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