Pivotal Gene for Puberty

"The neuroendocrine and genetic control of sexual maturation at puberty remains one of the great mysteries of human biology." (New England Journal of Medicine, Oct. 23, 2003)

Summary: A gene has been discovered that is needed for puberty. The gene is called GPR54, which stands for G protein-coupled receptor gene. Mutations in GPR54 gene were found that prevent a person from entering puberty. But giving the person some gonadotropin-releasing hormone lets them enter puberty. Complementary mouse studies indisputably established a pivotal role for GPR54 in puberty. GPR54 appears to regulate the secretion of gonadotropin-releasing hormone by the part of the brain called the hypothalamus and that hormone unleashes the pulsating cascade culminating in puberty.

Comment: And to think that this GPR54 gene may initiate all the throes of adolescence!

For more information, please see the following the MedicineNet.com Teen Center.

Barbara K. Hecht, Ph.D.
Frederick Hecht, M.D.
Medical Editors, MedicineNet.com


New Study Identifies Gene Signaling Puberty

Researchers have identified a gene that appears to be a crucial signal for the beginning of puberty in human beings as well as in mice. Without a functioning copy of the gene, both humans and mice appear to be unable to enter puberty normally. The newly identified gene, known as GPR54, also appears necessary for normal reproductive functioning in human beings.

The study appears in the October 23 issue of the New England Journal of Medicine. GPR54 is located on an autosomal chromosome (a chromosome that is not a sex chromosome).

"The discovery of GPR54 is an important step in understanding the elaborate sequence of events needed for normal sexual maturation," said Duane Alexander, M.D., Director of the National Institute of Child Health and Human Development (NICHD). "Findings from this study may lead not only to more effective treatments for individuals who fail to enter puberty normally, but may provide insight into the causes of other reproductive disorders as well."

Puberty begins when a substance known as gonadotropin releasing hormone (GnRH) is secreted from a part of the brain called the hypothalamus. Individuals who fail to reach puberty because of inherited or spontaneous genetic mutations are infertile.

"The discovery of GPR54 as a gatekeeper for puberty across species is very exciting" said the study's first author, Stephanie B. Seminara, of the Reproductive Endocrine Unit, Massachusetts General Hospital. "In the future, this work might lead to new therapies for the treatment of a variety of reproductive disorders."

The GPR54 gene contains the information needed to make a receptor. Receptors and the molecules that bind to them are analogous to a lock and a key mechanism. Like a key fits into a lock, certain molecules bind to their receptors, which usually sit atop a cell's surface. Once the binding takes place, the cell either will begin a new biochemical activity, or halt an ongoing activity. The researchers think that the molecule metastatin binds to the GPR54 receptor. As of yet, they do not know what precise effect the molecule may have on cells.

The researchers sought to learn which genes are involved in triggering the brain's release of GnRH at puberty. Two teams of researchers working independently of each other were involved in the discovery. One consisted of US based researchers, the other, of British researchers.

The US team included scientists from Massachusetts General Hospital, Brigham and Women's Hospital, and Harvard Medical School who collaborated with a researcher at Kuwait University. The British team included researchers from the University of Cambridge and Paradigm Therapeutics Ltd. in Cambridge.

The US researchers isolated the gene from members of a Saudi Arabian family that suffered from idiopathic hypogonadotropic hypogonadism (IHH), a rare inherited disease in which sexual development is incomplete or does not occur because of insufficient release of GnRH from the hypothalamus. If untreated, individuals with this disorder fail to develop sexually.

By analyzing genetic material from men and women with IHH, the US researchers first discovered that a certain region of chromosome 19 carried the mutant gene responsible for IHH. The researchers then identified GPR54 as the possible gene.

Working independently of the US. and Kuwaiti researchers, the British researchers created mice lacking GPR54. The mice without GPR54 also failed to reach puberty. The study authors found, however, that the brains of the mice contained normal levels of GnRH. The researchers do not yet know why the animals were unable to enter puberty, despite producing normal amounts of the hormone.

The findings from the two research teams complement each other, explained NICHD project officer Louis De Paolo, Ph.D, of NICHD's Reproductive Sciences Branch.

"Through some careful detective work, the US researchers pinpointed the gene that causes IHH in this family," said Louis De Paolo, Ph.D., project officer in NICHD's Reproductive Sciences Branch. "Using the mouse model, the British researchers gained an important insight into the function of the gene."

Source: National Institutes of Health (www.nih.gov)


Last Editorial Review: 10/23/2003




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