Research collaboration identifies gene essential to puberty
Scientists from MGH, Paradigm Therapeutics show gene is key in both humans and mice

BOSTON - October 22, 2003 - One of the great mysteries of human biology is what controls the timing and onset of puberty. By studying patients who fail to undergo puberty and using information made available by the Human Genome Project, American and British research teams have collaborated to identify a gene that appears to be a key regulator of puberty in humans and in mice.

In a report published in the October 23 New England Journal of Medicine, scientists from Massachusetts General Hospital (MGH) and from Paradigm Therapeutics and the University of Cambridge in the U.K. describe mutations in the gene for a protein called GPR54 that prevent both humans and mice from undergoing normal puberty and sexual maturation. This gene makes a receptor protein that probably is a key trigger of the hormonal cascade required for mammalian reproduction. The discovery could lead to new infertility treatments or contraceptive options, among other applications.

"It looks like we 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 director of the Harvardwide Reproductive Endocrine Sciences Center, one of three co-senior authors of the NEJM report. "Most other genes involved in reproductive control are species-specific, but this gene shows robust activity across two very different mammalian species."

The MGH effort - led by Stephanie Seminara, MD, of the Reproductive Endocrine Unit - began as a search for genes that cause idiopathic hypogonadotropic hypogonadism (IHH), a relatively unusual 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). In response to this secretion, the pituitary gland releases hormones called gonadotropins, which in turn stimulate the ovaries or testes to start releasing estrogen and testosterone. Individuals with IHH fail to experience normal puberty but can be treated with a variety of therapies, including subcutaneous injections of GnRH at levels that mimic the normal pulsations of this hormone from the hypothalamus, a therapy pioneered by Crowley's group at the MGH more than 20 years ago.

In their search for genes causing IHH, 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 affected and unaffected family members first showed linkage of the disorder to an area on chromosome 19. The researchers finally found that the gene that codes for GPR54 was mutated in all those with IHH and in none of the unaffected family members. Blood samples from unrelated normal individuals showed no mutations in the same gene, but analysis from other IHH patients revealed another individual - an African American male - who had different mutations in the gene.

About the time that the MGH team was further exploring the biology of GPR54, Seminara was contacted by researchers from UK biotechnology company Paradigm Therapeutics who had read the MGH team's previously published report linking an IHH gene to chromosome 19. Paradigm had already genetically engineered a group of mice in which the genes for 'orphan' receptor proteins (so named because their function was unknown) had been knocked out.

"They wanted to let us know 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 chromsome 19," says Seminara, an assistant professor of Medicine at Harvard Medical School. "They didn't have to tell me which gene had been knocked out; I knew it had to be same one that we had just identified."

"GPR54 is an exciting gene target whose role in the control of the sex steroid axis was unsuspected," says Samuel Aparicio, BM, BCh, PhD, of Paradigm and Cambridge, one of the report's co-senior authors. "These findings define a new drug target with wide potential for therapeutic intervention in conditions such as hormonal-dependent cancers, abnormal puberty and control of fertility." In keeping with their practice of nicknaming their knockout mice after famous orphans, the Paradigm group had already named these mice after fictional boy wizard Harry Potter.

The researchers note that GPR54 is probably not the only gene whose action is required for normal puberty but rather one of an ensemble of genes in charge of the complex process. Most of the unrelated IHH patients whose samples were screened in this study did not have mutations in that gene. But the fact that GPR54 plays such a strong role in both humans and mice indicates that its function is probably critical. "Our challenge moving forward will be to determine how directly this receptor affects the reproductive hormone cascade," says Seminara.

Along with Seminara, the report's co-first authors are Sophie Messager, PhD, of Paradigm, and Emmanouella Chatzidaki, BSc, of Cambridge; William Colledge, PhD, of Cambridge and Paradigm, is co-senior author. The study's other co-authors are James Acierno, BS, Jenna Shagoury, BS, Kristine Schwinof, MA, Susan Slaugenhaupt, PhD, and James Gusella, PhD, of the MGH; Rosemary Thresher, PhD, Alan Hendrick PhD, Dirk Zahn, PhD, John Dixon, BA, and Mark Carlton, PhD, of Paradigm; Stephen O'Rahilly, MD, of Cambridge, Wendy Kuohung, MD, and Ursula Kaiser, MD, of Brigham and Women's Hospital; and Yousef Bo-Abbas, MD, of Kuwait University.

The research was supported by grants from the National Institute of Child Health and Human Development, National Center for Research Resources, National Institute of General Medical Studies and the Ford Physiology Fund Endowment.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $350 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neuro-degenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.

Media Contact: Sue McGreevey, MGH Public Affairs
Linda Millett, Paradigm Therapeutics

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