The sequence of events started innocently enough. Some of the mice that Miner was breeding for his kidney research were born with a strange appearance. Instead of having the usual folds and creases, their skin was abnormally tight and thick. The researchers called it "wrinkle-free."
The effect was not unlike that seen in humans with a rare genetic disorder called restrictive dermopathy. These mice, like humans with the disease, had difficulty breathing and died soon after being born.
"It was a novel, unexpected line of mutant mice that had occurred completely accidentally," says Miner, an associate professor of medicine, cell biology and physiology at Washington University School of Medicine in St. Louis. He is senior author of a paper on the topic appearing in the March 7-11 issue of the Proceedings of the National Academy of Sciences.
Such accidents happen all the time in research labs and, for all these scientists knew, this was a characteristic that occurred all the time in mice. Still, Miner and his colleagues decided to investigate. They discovered that, far from being common, "these weren't mice that anyone had seen before."
They then set out to identify the exact gene that was responsible for the mutation, and were met with yet another surprise. The gene turned out to be Slc27a4, which was presumed to be involved in obesity because it produces a protein called FATP4 (fatty acid transport protein 4), which may play a role in transporting fatty acids.
The protein is already a target for experimental anti-obesity drugs. Now it appears the gene also plays a part in skin development and hair growth. "Nothing was known about its role in hair growth or skin development," Miner says. "Our experiments demonstrate for the first time that SLc27a4 is involved in skin development and hair growth."
As it turns out, when skin samples from the wrinkle-free mice were grafted onto healthy animals, they produced much less hair than skin grafts from normal mice.
"We're beginning to identify genes that encode certain proteins that we probably didn't initially expect," says Duane Eichler, professor of biochemistry and molecular biology at the University of South Florida in Tampa. "The particular protein they're looking at, its major role is in the transport of fatty acids across membranes so it looks sort of boring -- but it turns out that the process is highly regulated."
And because it's highly regulated, many things can go wrong. Identifying and fixing those areas provides grist for future research, Eichler says.
"It's going to provide a whole new area of investigation for researchers who are interested in skin and hair development because the importance of fatty acids and lipid metabolism is now much more than was predicted," Miner predicts. "Not that no one else has shown that fatty acids are involved in skin, but no one has seen such a dramatic effect as we have seen with this single mutation in fatty acid transport."
Miner isn't sure how the gene affects skin development, but he has a hypothesis. During normal development, the skin forms a barrier to keep water in the body and harmful substances out. Mice with the FATP4 mutation did not fully develop this barrier, but had skin that was about three times as thick as normal. Miner thinks the extra-thick skin may have been an attempt to compensate for the lack of a barrier.
The body also requires lipids (a class of molecules that includes fatty acids) to develop the skin's natural barrier, which occurs late in embryonic development. Miner's findings suggest that the skin and hair deficiencies might occur much earlier.
Miner hopes the discovery eventually has a bearing on individuals with restrictive dermopathy. "We're looking for mutations in three patients that have that disorder, but we haven't found any yet," he says.
The findings also suggest that if anti-obesity drugs inhibit FATP4, there might be side effects, some that patients might want (less wrinkling) and some they can live without (more hair loss).
Miner and his colleagues have applied for a patent for the use of inhibitors to FATP4 that might prevent wrinkling or hair growth.
For more on restrictive dermopathy, check out the Doctor's Doctor. Learn about obesity from the American Obesity Association or the North American Association for the Study of Obesity.