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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