What's New: Hot Topics - Male Fertility

Researchers delve into DAZ to expand fertility Tx.
UROLOGY TIMES Issue: Jan, 1999

Potter Wickware UT Correspondent San Francisco-Scottish investigators are working to better understand the process of gametogenesis and activity patterns in fertility genes-research that will ideally lead to new therapies for infertile patients. Several gene families on the human Y chromosome are known to be involved with spermatogenesis, Howard J. Cooke, PhD, reported at the American Society for Reproductive Medicine meeting here.

Dr. Cooke is head of chromosome biology at the Medical Research Council and a member of the human genetics unit at Western General Hospital, Edinburgh, Scotland. One of those gene families encodes the RNA-binding protein DAZ ("deleted in azoospermia"), which maps to the AZFc region of the Y chromosome. DAZL-the autosomal ancestor of DAZ-maps in humans to 3p25 and is highly homologous from flies to humans, indicating a general function conserved through evolution, said Dr. Cooke.

"DAZ and DAZL are also highly homologous to each other, differing only in the presence of multiple repeats in DAZ of a region in DAZL," he said.

"The only known variation in DAZ is in the number of copies of the gene in some individuals." There may be age-dependent changes in the pattern of DAZ expression, Dr. Cooke noted.

The average deletion frequency of the AZFc region in azoospermic males is between 5 and 10%, but there are problems in interpreting missing AZFc. For example, the phenotype of individuals with the same deletion is variable, and the frequency of these deletions is relatively high. Given their association with infertility, they most commonly appear de novo. That, in turn, raises the possibility that germ line mosaicism or deletions occurring during spermatogenesis could appear in otherwise normal fathers having sons with deletions on their Y chromosomes, Dr. Cooke said.

Dr. Cooke's group has found that DAZL is a germ cell-specific protein expressed during the diploid stages of spermatogenesis and in oocytes. It is not present in the nucleus but is localized in the cytoplasm of germ cells from the embryo through adulthood. In mice, DAZL is necessary for germ-cell survival and gamete development in both sexes. Using antibodies to DAZ, Dr. Cooke and colleagues have been able to look at testicular and ovarian histology and suggest that the protein controls the availability of RNA, thereby regulating protein production in the gonads. The necessity of the DAZL protein for male and female fertility in the mouse suggests that this could be a target for contraceptive development using compounds that stopped the protein from binding to RNA. In men lacking DAZ genes, experiments in mice suggest fertility might be restored if the level of protein produced by the DAZL gene was increased.

Another line of research uses knockout mice to study the contribution of DAZL to fertility. Homozygous knockout males have small testes and minute ovaries, which are devoid of germ cells. Heterozygous females have largely normal ovaries, while heterozygote males have abnormal sperm, though not enough to affect fecundity. UT.

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