October 24, 2003

Advances
Gene essential to puberty identified

By studying patients who fail to undergo puberty, MGH researchers and collaborators from Britain have identified a gene that appears to be a key regulator of puberty in humans and in mice.

In the Oct. 23 New England Journal of Medicine, the scientists describe how mutations in the gene for a protein called GPR54 prevent both humans and mice from undergoing normal sexual maturation. This could lead to applications such as new infertility treatments or contraceptive options.

" We may have found a key genetic gatekeeper of puberty in mice and men," says William Crowley Jr., MD, chief of the MGH Reproductive Endocrine Unit, and
co-senior author.

The MGH effort — led by Stephanie Seminara, MD, of the Reproductive Endocrine Unit — began as a search for genes that cause a disorder in which puberty does not occur at the usual age. Normal puberty begins when the hypothalamus, a structure deep within the brain, begins to secrete gonadotropin-releasing hormone (GnRH). Patients with this particular disorder (called IHH) fail to experience normal puberty but can be treated with therapies including subcutaneous injections of GnRH at levels that mimic normal pulsations of the hormone from the hypothalamus, an approach pioneered by Crowley's group at the MGH more than 20 years ago.

Seminara and her colleagues identified a family from Saudi Arabia in which many individuals of both sexes failed to undergo puberty. Analysis of blood samples from this family first linked the disorder to an area on chromosome 19 and finally showed that the gene that codes for GPR54 was mutated in the affected family members. Blood samples from unrelated patients with IHH revealed another individual who had different mutations in the same gene.

About the time that the MGH team was further exploring the biology of GPR54, Seminara was contacted by researchers from the UK company Paradigm Therapeutics. They had already genetically engineered a group of mice in which the genes for proteins of then-unknown function had been inactivated. "They told us that they had a strain of 'knockout' mice that appeared to have IHH. The human version of the mouse gene that they had just knocked out was known to reside in our linked region on chromosome 19," says Seminara. "I knew it had to be the same gene that we had just identified."

The researchers note that GPR54 is probably only one of a series of genes required for normal puberty. Other MGH co-authors are James Acierno, Jenna Shagoury, Kristine Schwinof, Susan Slaugenhaupt, PhD, and James Gusella, PhD.