Genetic 'Pilot Light' for Puberty Found
Appears to control key hormone signals that lead to sexual maturity
WEDNESDAY, Oct. 22, 2003 (HealthDayNews) -- Researchers have identified a genetic "pilot light" for puberty in both mice and humans.
Defects in the gene, called GPR54, ultimately bottleneck the chemical cascade necessary for breaking voices, acne and the litany of other changes that herald the arrival of sexual maturity. The absence of these hormones retards the formation of normal sex organs, including testes and ovaries. Some patients also experience an inability to smell, small size and other hormone-related problems.
"It certainly appears to be an important gene in the regulation and the timing of puberty in the human," says study leader Dr. Stephanie Seminara, an endocrinologist at Harvard Medical School.
The discovery falls out of an analysis of a large Saudi Arabian family in which three sets of first cousins married. Doctors learned six of the couples' 19 children were afflicted with a rare genetic disorder known as idiopathic hypogonadotropic hypogonadism (IHH), a condition marked by low levels of sex hormones and suppressed sexual development.
IHH results from problems with gonadotropin, a family of hormones produced in the brain's pituitary gland. The problem really begins a step earlier, however, since the pituitary relies on a signal from another brain region, the hypothalamus, to kick into action.
Puberty is thought to begin when the hypothalamus starts secreting gonadotropin-releasing hormone (GnRH), stimulating the pituitary to produce gonadotropins, which in turn spur the ovaries and testes to release estrogen and testosterone, respectively.
Seminara and her colleagues used a variety of gene technologies in their study. They analyzed DNA samples from the family members and found errors in the GPR54 gene. None of the family members without the disorder had defects in the gene, which controls a receptor in the hypothalamus.
The researchers then showed that mice missing the mouse version GPR54 developed the rodent form of IHH -- which the researchers could correct with hormone injections. Significantly, the animals, provided by the British biotech firm Paradigm Therapeutics, have normal amounts of gonadotropin-releasing hormone in their hypothalamus. "This suggests that the problem is with GnRH processing, or release," Seminara says.
A report on the research appears in the Oct. 23 issue of the New England Journal of Medicine. Scientists from Paradigm Therapeutics and the University of Cambridge, England, collaborated on the study.
GPR54 is almost certainly not the only gene whose proper function is crucial to puberty. Genetic tests of other people with IHH unrelated to the Saudi family found that only one, a black American man, had mutations in GPR54, but these differed from the errors in the Saudi patients.
In fact, the Boston scientists weren't the first to discover that errors in GPR54 delay puberty. That honor goes to a group of French researchers, led by Dr. Nicolas de Roux, who reported their findings last month in the Proceedings of the National Academy of Sciences. De Roux, of the French Institute of Health and Medical Research in Paris, says the supporting evidence in mice from Seminara's group "completely confirmed" his own results.
The two papers taken together are "very important" for understanding how puberty works in humans, de Roux says. That knowledge may lead to new drugs to treat a variety of hormonal conditions. Only by decoding the exact mechanism of GPR54 will scientists reap any therapeutic benefits from the gene, he adds.
In addition to helping patients with insufficient sex hormones, the research could also lead to treatments for children who undergo puberty too early, Seminara says.