Portland, Ore.
In a discovery that also has application to a wide range of genetic diseases, such as hypercholesterolemia and diabetes insipidus, P. Michael Conn, Ph.D., the Oregon National Primate Research Center’s associate director and a special assistant to Oregon Health & Science University President Peter Kohler, M.D., has uncovered the cause of and, potentially, the cure for a rare form of male infertility.
Conn announced this week at the Endocrine Society’s annual meeting (ENDO 2002) in San Francisco that the disorder, hypogonadotropic hypogonadism (HH), results from a mistake in the protein folding process of a critical receptor in the pituitary gland. He and his laboratory colleagues, Jody Janovick and Lupita Maya-Nuñez, have also demonstrated that a drug can rescue the errant protein and make it function normally.
The full study will be published in the July 2002 issue in the Journal of Clinical Endocrinology and Metabolism. The article is one of 125 selected from more than 2,500 abstracts submitted to ENDO 2002 to be included in the research summaries book, a resource for the media during ENDO 2002 and throughout the year.
A receptor, which may be thought of as a lock, allows an outside ligand, or key — in this case, a brain hormone called gonadotropin releasing hormone (GnRH) — to activate a response from a cell. Located on the cell membrane or surface, the receptor is a string of precisely folded amino acids. Even a slight defect in folding, Conn found, may send a molecule to the wrong place in the cell, where the ligand can’t reach it — in effect, a lock beyond the reach of its key.
In healthy people, GnRH binds to the pituitary gland at the base of the brain, stimulating it to release hormones that, in turn, activate the ovary and/or testis. The receptor in the pituitary gland that binds GnRH comprises a long string of 328 amino acids that cross the membrane seven times.
Before Conn’s discovery, it was presumed that in cases of HH, a mutant molecule cannot bind GnRH or initiate the cascade of molecular changes that result in sperm maturation. Conn found, instead, that diverse mutant molecules causing HH in several patients are all fully functional but, as a result of a folding mistake, they have been misrouted in the cell. "The parts are good," commented Conn, "but just in the wrong place."
Using a drug designed by Merck and Company, Conn and his associates were able to rescue the stray mutant molecules by causing the receptor to fold correctly. Their success suggests that pharmaceutical archives already contain other compounds potentially valuable for their ability to rescue molecules sent off in the wrong direction by folding errors.
Among other genetic diseases that result from misfolded, but otherwise competent, molecules are cystic fibrosis, nephrogenic diabetes insipidus, retinitis pigmentosa and hypercholesterolemia.
GnRH is used to decrease steroid hormones in cases of breast and prostate cancer, to increase those hormones in cases of HH and crypto-orchidism, and for animal health and reproduction. Understanding its receptor will lead to new treatments for HH, and understanding effector coupling will lead to new and better drugs.
Conn’s method of determining the competency of mutant molecules depended on years of previous animal research with rat pituitary cells. During the past year, Conn, who is a past-president of the Endocrine Society, has been targeted by animal rights extremists and by People for the Ethical Treatment of Animals (PETA).
According to William F. Crowley, M.D., director of clinical research, Massachusetts General Hospital of Harvard University and president of the Endocrine Society, "The judgment of scientific peers around the country about Dr. Conn’s remarkable discovery is convincing evidence of the value of his work in giving hope to patients, and the importance of animal research in furthering knowledge about human and animal health."
This study was supported by the National Institutes of Health and The Fogarty International Center’s International Training and Research Program in Population and Health.
Conn announced this week at the Endocrine Society’s annual meeting (ENDO 2002) in San Francisco that the disorder, hypogonadotropic hypogonadism (HH), results from a mistake in the protein folding process of a critical receptor in the pituitary gland. He and his laboratory colleagues, Jody Janovick and Lupita Maya-Nuñez, have also demonstrated that a drug can rescue the errant protein and make it function normally.
The full study will be published in the July 2002 issue in the Journal of Clinical Endocrinology and Metabolism. The article is one of 125 selected from more than 2,500 abstracts submitted to ENDO 2002 to be included in the research summaries book, a resource for the media during ENDO 2002 and throughout the year.
A receptor, which may be thought of as a lock, allows an outside ligand, or key — in this case, a brain hormone called gonadotropin releasing hormone (GnRH) — to activate a response from a cell. Located on the cell membrane or surface, the receptor is a string of precisely folded amino acids. Even a slight defect in folding, Conn found, may send a molecule to the wrong place in the cell, where the ligand can’t reach it — in effect, a lock beyond the reach of its key.
In healthy people, GnRH binds to the pituitary gland at the base of the brain, stimulating it to release hormones that, in turn, activate the ovary and/or testis. The receptor in the pituitary gland that binds GnRH comprises a long string of 328 amino acids that cross the membrane seven times.
Before Conn’s discovery, it was presumed that in cases of HH, a mutant molecule cannot bind GnRH or initiate the cascade of molecular changes that result in sperm maturation. Conn found, instead, that diverse mutant molecules causing HH in several patients are all fully functional but, as a result of a folding mistake, they have been misrouted in the cell. "The parts are good," commented Conn, "but just in the wrong place."
Using a drug designed by Merck and Company, Conn and his associates were able to rescue the stray mutant molecules by causing the receptor to fold correctly. Their success suggests that pharmaceutical archives already contain other compounds potentially valuable for their ability to rescue molecules sent off in the wrong direction by folding errors.
Among other genetic diseases that result from misfolded, but otherwise competent, molecules are cystic fibrosis, nephrogenic diabetes insipidus, retinitis pigmentosa and hypercholesterolemia.
GnRH is used to decrease steroid hormones in cases of breast and prostate cancer, to increase those hormones in cases of HH and crypto-orchidism, and for animal health and reproduction. Understanding its receptor will lead to new treatments for HH, and understanding effector coupling will lead to new and better drugs.
Conn’s method of determining the competency of mutant molecules depended on years of previous animal research with rat pituitary cells. During the past year, Conn, who is a past-president of the Endocrine Society, has been targeted by animal rights extremists and by People for the Ethical Treatment of Animals (PETA).
According to William F. Crowley, M.D., director of clinical research, Massachusetts General Hospital of Harvard University and president of the Endocrine Society, "The judgment of scientific peers around the country about Dr. Conn’s remarkable discovery is convincing evidence of the value of his work in giving hope to patients, and the importance of animal research in furthering knowledge about human and animal health."
This study was supported by the National Institutes of Health and The Fogarty International Center’s International Training and Research Program in Population and Health.
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