New York, NY April 7, 1999– Researchers at Columbia University College of Physicians and Surgeons have discovered that a genetic mutation associated with hair loss in nude mice may also have implications in human immune diseases. The study could lead to more amenable therapies for hair loss and more effective treatments for primary immunodeficiency diseases.
The research, reported in the April 8 issue of Nature, identifies a second human gene associated with hair loss and sheds light on the thymus’s crucial role in the immune system.
“The nude mouse is used everywhere,” says Dr. Angela Christiano, who in 1998 discovered the first human gene associated with hair growth, called “hairless.” “This is the first time the genetic mutation associated with the nude mouse has been implicated in a human disease. It’s also the first time that an immune deficiency has been associated with a gene expressed in an organ (the thymus), rather than in cells of the bloodstream.”
In 1996, Italian researcher Claudio Pignata of Federico II University in Naples described a mother in a small village in southern Italy who twice gave birth to girls with no hair on their bodies and severely depressed immune systems. One died within 12 months, but the other is alive after receiving a bone marrow transplant from her healthy brother.
After reading Pignata’s research on the two girls in a clinical genetics journal, Christiano and research fellow Jorge Frank contacted Pignata to obtain blood samples from the family for DNA studies. Since the nude mouse is so widely used and well characterized, they knew that its condition arises from a mutation in the whn gene, a transcription factor that is expressed in the thymus and skin. When the researchers sequenced the human whn gene in the two girls, they found that it contained the same mutation as the nude mouse, which results in a truncated RNA that is digested before it can be translated into a protein.
As a result of the mutation, it is believed that cells in both the thymus and skin fail to fully differentiate. In the skin of mammals, the gene is normally expressed in the developing hair matrix cells which grow into a thick, hardened hair. Without it, both people and mice grow no hair or just a few stunted ones that rarely emerge from the skin surface. In contrast to the problems resulting from a mutated hairless gene, defects in the whn gene do not cause any defects in the hair follicle itself; it is fully developed and capable of producing hairs if the whn gene can be turned on.
“This defect is more amenable to therapy,” says Christiano. She is currently conducting gene therapy experiments that attempt to introduce a functional whn gene into hair follicles to see if she can grow hair on a nude mouse. “This discovery extends our understanding of genes involved in hair growth and brings us closer to approaching more common forms of hair loss, such as male pattern baldness,” adds Christiano.
Of potentially broader impact is the light her findings shed on the thymus and the immune system. The thymus, a small organ just above the heart, plays a crucial role in the development of T cells, which recognize foreign substances in the body and initiate an immune response. Immature T cells develop in the bone marrow, then migrate to the thymus for “education.” The thymus kills off any T cells that might recognize native substances of the self as foreign. It lets only ones that recognize foreign substances mature and move into the bloodstream.
In mice, the whn gene appears to play a role in the development of the thymus, which is arrested when the gene is mutated. X rays of the two girls showed no evidence of a thymus. The lack of a thymus apparently prevented any of the girls’ T cells from maturing, thus preventing the girls from mounting an effective immune response. “The T cells are normal, but they lack a thymus to educate them,” says Pignata. Before this discovery all genetic immune diseases were related to defects in the T cells and B cells themselves.
Autoimmune diseases, such as lupus and rheumatoid arthritis, arise when faulty T cells attack a person’s own tissue. Christiano says that the whn gene might one day be used to rejuvenate the thymus, which degenerates in childhood, so that it could reeducate the T cells and eliminate the faulty ones.
Christiano believes that many healthy residents of the town in Italy may carry one copy of the mutated whn gene. People suffer alopecia and immune suppression only when they have two copies of the gene, having received one from each parent. Dr. Pignata is looking into population and prenatal screening, which might be able to prevent the future birth of such seriously ill children.
The report’s other authors are Andrei A. Panteleyev, David M. Prowse, Howard Baden, Lorin Weiner, Lucia Gaetaniello, Wasim Ahmad, Nicola Pozzi, Peter B. Cserhalmi-Friedman, Vincent M. Aita, Hendrik Uyttendaele, Derek Gordon, Jurg Ott and Janice L. Brissette.
The research was funded in part by the National Alopecia Areata Foundation.