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Hair loss syndrome created in mice

17.06.2002


Finding may help explain related conditions in people



Inactivating just one of more than two dozen similar genes can cause temporary but profound hair loss, known as alopecia, in mice, researchers from Johns Hopkins and the Pasteur Institute in France report in the June issue of Genes & Development.
Surprisingly, the impact of loss of this keratin 17 gene (K17) depended on an animal’s genetic make-up: its loss caused no effect in one strain of mice and complete alopecia in another, the scientists report. Mice that were a mix of the strains showed severe or moderate hair loss, or even no hair loss at all, says Pierre Coulombe, Ph.D., professor of biological chemistry at the Johns Hopkins School of Medicine.

"It’s well known that a single genetic change can cause different effects in different individuals," says Coulombe, also a faculty member in dermatology. "However, it’s unusual to be able to unravel why this happens. If we can understand how mice respond differently to the lack of K17, maybe it will help us understand what’s going on in humans with altered K17."



In people, a single genetic mutation in K17 causes two very rare, clinically distinct conditions, one involving the skin’s oil-producing glands, and the other the fingernails. No one has been able to explain how two such different conditions can result from a single change in the K17 gene and protein.

There are roughly 50 or so keratin proteins that help build the hair, nails and glands found in the skin in people, says Coulombe. Of these, about 30 are involved in specific diseases, many of which are as variable as what’s seen with K17. While they haven’t examined samples from people, the scientists suggest their results may affect research into keratin diseases in humans.

"We’ve documented in mice a clear example, specific to one structure -- hair -- and one gene, in which genetic background has a profound impact on the severity of a condition," says Coulombe. "It raises the possibility that the genetics of a person might explain variability in human keratin diseases."

In mice that kept their hair in the absence of K17, a related molecule, keratin 16 (K16), took up the slack, the scientists found. "Mice that lost hair failed to compensate for K17; K16 didn’t step in," says Coulombe, a researcher in the school’s Institute for Basic Biomedical Sciences. "What triggers K16 to make up for K17 in certain mice and not in others? The answer is going to be more complex than K16 itself."

The findings raise the possibility that proposed gene therapy for keratin-related diseases, or potentially others, could be less precise in their application than expected, says Coulombe.

"People talk about gene therapy as ’molecular genomic surgery,’ as going in to the genetic information and slicing out what’s wrong and inserting a corrected version," he explains. "But this study shows we may not need to be so sophisticated. For K17 diseases, for instance, perhaps it would be possible to identify and increase production of a compensatory keratin, without causing negative effects, and alleviate the condition."

In the original group of mice, each a cross of strains 129/Sv and C57Bl/6, animals were born with normal hair. By 5 days of age, some of the mice lacking K17 failed to grow their first round of postnatal hair. By three weeks of age, however, when the second cycle of hair production in mice begins, even the most severely affected mice re-grew hair and appeared normal.

In subsequent experiments, the scientists discovered that pure 129/Sv mice were not affected by the loss of K17, while pure C57Bl/6 mice lost all their hair. The 129/Sv mice somehow stimulated K16 to make up for the lack of K17, they found.

The results also help reveal K17’s role in hair follicles in mice. Hair loss was due primarily to two flaws caused by the lack of K17: weaker strands of hair and a propensity for a key part of the hair follicle to die. Because all mice re-grew hair, even if K16 wasn’t stimulated, K17 is more important in the first hair cycle after birth than subsequent hair cycles, the researchers report.


The studies were funded by grants from the U.S. National Cancer Institute, the U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases, the French National Center for Scientific Research (CNRS) and the Pasteur Institute, Paris. Other authors on the report are co-first authors Kevin McGowan and Xuemei Tong of the Johns Hopkins School of Medicine; Emma Colucci-Guyon, Francina Langa and Charles Babinet of the CNRS and Pasteur Institute.

Joanna Downer | EurekAlert
Further information:
http://www.genesdev.org

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