October 01, 1995
Searching the Y chromosome for a "house with green shutters"
A team of U.S. and Finnish scientists has found that a specific
defect in the Y chromosome may be responsible for 13 percent of cases
of azoospermia, the inability to make sperm and the most severe form of
male infertility.
This 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. The research, reported in the August
issue of Nature Genetics, was led by David Page, an HHMI
investigator at the Whitehead Institute for Biomedical Research.
“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.”
David C. Page
The researchers examined the Y chromosome of 89 men with azoospermia
and found that 12 of the men were missing a tiny fragment of the
chromosome's long arm. These men were otherwise healthy and showed no
signs of physical obstruction in their reproductive tract. The fathers
of the men had Y chromosomes intact in this region as did 90 fertile
men studied for comparison. Based on these observations, Page and his
colleagues concluded that azoospermia resulted from a newly arising
mutation in the Y chromosome and that a gene (or genes) located in the
missing region is required for sperm production.
"Despite medical advances in treatment, there are many couples who
never learn the cause of their infertility," said Page, who also led
the team that 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, the HHMI scientists 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. When they found that
a significant number of infertile men were missing a common region,
they began to scrutinize that region. So far, the team has found a
single gene, DAZ (deleted in azoospermia), in the common deleted
region. Page said, however, that they don't yet know if this gene is
the long-sought azoospermic factor required to make sperm. Scientists
have suspected that the Y chromosome carries such an azoospermic
factor, but the precise molecular identity of that factor remains
unknown.
The Y chromsome map helped Page and his colleagues narrow the search
for the gene to a small region on the chromosome. "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," Page said. "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."
Infertility affects nearly 10 percent of all Americans, 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 lingering
effects of bacterial and viral infections. Two percent of all males,
however, have no such abnormalities and are otherwise healthy except
that they do not produce new sperm (azoospermia) or they produce only
few or deformed sperm (oligospermia).
The HHMI team, together with Sherman Silber of St. Luke's Hospital
in St. Louis, Mo., also studied biopsies of the testes of the men with
the Y deletion. Their studies revealed that although none of the men
produced mature sperm, some were capable of making immature sperm
cells. In addition, the biopsies showed surprisingly variable
testicular manifestations, even with similar deletions; what had been
viewed as distinct clinical disorders may actually have a common
cause.
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