Genetic Factors May Account for Infertility in Otherwise Healthy Males

CAMBRIDGE, Mass. — A team of U.S. and Finnish scientists has found that a specific defect in the male sex chromosome (the Y chromosome) may be responsible for 13 percent of cases of azoospermia, the complete inability to make sperm and the most severe form of male infertility. The study is one of the first to demonstrate that genetic defects can sometimes explain infertility in otherwise healthy couples and could lead to a better understanding of the molecular mechanisms required to make healthy sperm. This research, reported in the August issue of Nature Genetics, was led by Dr. David Page of the Whitehead Institute for Biomedical Research and the Howard Hughes Medical Institute (HHMI).

The researchers examined the Y chromosome of 89 men with azoospermia and found that 12 were missing a tiny fragment of the long arm of the Y chromosome. These men were otherwise healthy and showed no signs of physical obstructions in their reproductive tract. The fathers of these men had Y chromosomes intact in this region as did 90 fertile men, who were studied for comparison. Based on these findings, the researchers concluded that the azoospermia resulted from a newly arising mutation in the Y chromosome and that a gene (or genes) located in the missing region is required to make healthy sperm.

“Despite medical advances in treatment, many couples never learn the cause of their infertility,” says Dr. Page, who along with his colleagues completed the first comprehensive map of the Y chromosome in 1992. “Little attention has been paid to the possibility that fertility problems can have a genetic basis. Our findings will help some couples get a definitive answer about the reasons for their infertility and may eventually lead to new directions in infertility therapy.”

In this study, first author Dr. Renee Reijo and her Whitehead/HHMI colleagues meticulously combed the Y chromosomes of the infertile men for missing DNA landmarks, using the 1992 physical map of the Y chromosome as a guide. Once they found that a significant number of infertile men were missing a common region, they began scrutinizing that region. So far, they have found one gene, DAZ (deleted in azoospermia), in the commonly deleted region. However, they don’t yet know if this gene is the long-sought azoospermic factor required to make sperm. Scientists have long suspected that the Y chromosome carries such an azoospermic factor, but the precise molecular identity of that factor has so far eluded researchers.

The Y chromosome map helped Dr. Page and his colleagues narrow down the location of the gene to a small region on the chromosome-the equivalent of narrowing the location of a house down to one city block. “Finding the DAZ gene within this region is the equivalent of locating a friend’s house when you know it has green shutters and stands within one city block of an important landmark,” says Dr. Page. “The DAZ gene appears to be a reasonable candidate for the azoospermic factor, but more studies will be required to determine whether it is the only house on the block with green shutters. There may be others that we haven’t seen yet.”

Dr. Page’s collaborators include Dr. Reijo and research groups led by Dr. Albert de la Chapelle of the University of Helsinki in Finland and Dr. Sherman Silber of St. Luke’s Hospital in St. Louis, Mo.

Some 10 percent of all Americans (about 1 in 6 couples) are infertile, and each year as many as 20,000 couples undergo in vitro fertilization in the hope of conceiving. The causes of infertility range from physical abnormalities in the male or female reproductive tracts to aftereffects of bacterial and viral infections. However, 2 percent of all males have no "plumbing problems" and except for the inability to produce any sperm (azoospermia) or few or deformed sperm (oligospermia), are otherwise healthy. This research shows that infertility in men with azoospermia can have a genetic basis.

The Whitehead/HHMI team, together with Dr. Sherman Silber, also studied biopsies of the testes of the men with Y deletions. These studies revealed that although none of the men produced mature sperm, some were capable of making immature sperm cells. In addition, the biopsies showed varying clinical manifestations, even with similar deletions, indicating that the same deletion could cause azoospermia in different ways, disrupting at different stages the process of the making of sperm.

This work was funded in part by grants from the National Institutes of Health, the Howard Hughes Medical Institute, and the Damon Runyan/Walter Winchell Foundation.