A genetic mutation appears to produce eyelid defects in newborns and trigger early onset of menopause decades later. The finding could help researchers decipher how genetic processes during fetal development can have immediate manifestations at birth and also lead to certain age-associated changes later in life. The newly identified gene, called FOXL2, is required for the normal eyelid development in newborns. In women, FOXL2 is also needed to form a full complement of eggs in the ovaries before birth. If it is mutated, babies may be born with a drooping eyelid condition called blepharophimosis, and certain women born with this condition may also experience premature menopause.
The discovery is the first to pinpoint a gene responsible for early onset of menopause, said David Schlessinger, Ph.D., chief of the NIA's Laboratory of Genetics in Baltimore. FOXL2 was isolated from a region of chromosome 3 that had been implicated in families with a history of blepharophimosis and premature ovarian failure. The gene was cloned by Italian scientists led by Giuseppe Pilia of the University of Cagliari, with the assistance of French researchers and NIA investigators.
The finding, published in the February 2001 issue of Nature Genetics, establishes blepharophimosis as a potential marker for early onset of menopause in some women, said Dr. Schlessinger, a coauthor of the study. The discovery also may shed light on certain aspects of aging, which may be driven by genetic processes that begin soon after conception.
"It's becoming increasingly clear that early events in embryonic and fetal life are important for what happens later during aging," Dr. Schlessinger said. "It was once thought that life was composed of hermetically sealed compartments. First, there was infancy, which was followed by young adulthood. Then, after development was complete and you were a mature adult, you started to age. Now it is clear that things don't work that way. Aging, like other biological processes, has genetic determinants that are initiated in utero."
Early onset of menopause, also known as premature ovarian failure, is a prime example of these genetic forces at work, Dr. Schlessinger said. During normal fetal development, eggs are formed in the ovaries. Before birth, the vast majority of these eggs are naturally destroyed because they are flawed or fail to flourish. But usually a woman is born with enough eggs to sustain fertility for several decades of her adult life.
Typically, menopause occurs in a woman's late 40s or early 50s. However, premature ovarian failure occurs in up to one percent of women before age 40. Radiation therapy, chemotherapy, and autoimmune disorders, in which antibodies damage the ovaries, can trigger premature ovarian failure. But up to 30 percent of women with premature ovarian failure have at least one female relative with the same condition, strongly suggesting many cases might be inherited. However, before the discovery of FOXL2, the gene or genes responsible for this condition were unknown.
FOXL2 is a transcription factor, meaning it stimulates other genes to turn "on" or "off" in the eyelids and ovaries at appropriate times. A mutation in one of the two copies of this gene disrupts this process, so genes that would normally be activated by FOXL2 remain dormant, inactive genes might be inappropriately activated, or both. As a consequence, affected women may be born with blepharophimosis and may have fewer egg follicles than necessary to sustain a normal reproductive lifespan.
"Although we are talking about an age-related condition, menopause, all of the critical events have occurred in fetal development that determine when menopause will occur," Dr. Schlessinger said. "If we understand more about how tissues are formed, we might be able to prolong the function of cells and even regenerate tissues that are worn out."
In the next phase of research, investigators will likely look for the underlying mechanisms that cause women with this genetic mutation to produce fewer eggs, Dr. Schlessinger said. The mutation, for instance, may arrest normal egg follicle development so that fewer of them form in the ovaries. It's also possible that egg follicles develop normally, but some action triggered by the mutant FOXL2 unnecessarily destroys many of them.
The NIA, one of 25 institutes and centers comprising the National Institutes of Health (NIH), leads the federal effort supporting and conducting research on aging and age-related diseases and special needs of older people.