You're not likely to encounter a very rare disease called pachyonychia congenita. As its name suggests, pachyonychia thickens fingernails or toenails to elephantine dimensions. Another strangely related malady, steatocystoma multiplex, is a cyst with sebaceous gland cells in its wall. (Sebaceous glands in the skin's dermis open into the hair follicles.)

"In people," observed skin cell biologist Pierre Coulombe, "a single genetic mutation in the keratin 17 [K17] gene causes those clinically distinct conditions. No one has been able to explain how two such different conditions can result from a single change in K17.

"Keratin is the family name for a group of proteins in epithelial cells," Coulombe continued. "There are roughly 50 keratin proteins that help build the hair, nails and skin glands in people. Of these, about 30 are involved in specific diseases, many of which are as variable as what we see in K17."

Coulombe, a professor of biological chemistry and dermatology at Johns Hopkins School of Medicine in Baltimore, is senior author of a paper in the June issue of Genes & Development, published by Cold Spring Harbor Laboratory. The journal's title: "Keratin 17 null mice exhibit age- and strain-dependent alopecia."

Hair Formation, Integrity Rely On K17 Protein

"The main message of our paper," Coulombe told BioWorld Today, "is that of the 30 or so keratins found in hair follicles, one plays a critical role in the formation and structural integrity of the hair. The phenotypic variations that we see in mice," he went on, "might be related to the same variability that we see in the human population. There the same mutation can cause various clinical presentations, including perhaps those fingernail and sebaceous gland disorders. These patients have minimal nail alterations, but they do show some hair changes.

"In the human population," Coulombe noted, "people have missense mutations in their K17 gene. That is, of the 432 amino acids that make up the K17 protein chain, one of them - a point mutation - is substituted for another. Its protein is still made but it has a different amino acid at one position. It's not a complete loss of function, whereas the K17 knockout we've done in mice creates a complete loss of function. What we've done in our mice is to inactivate their K17 gene. We removed it so there is no K17 protein anywhere in those mice.

"Surprisingly," Coulombe continued, "the impact of loss of this keratin 17 gene depended on an animal's genetic makeup: Its loss caused no effect in one strain of mice and complete alopecia [baldness] in another. KO mice that were a mix of genetic strains showed severe or moderate hair loss, or even no hair loss at all," he added. "It's well known that a single genetic change can cause different phenotypic effects in different individuals. If we can understand how mice respond differently to the lack of K17, maybe it will help us comprehend what's going on in humans with altered K17.

"In the original group of experimental mice," Coulombe recounted, "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 3 weeks of age, however, when the second hair production cycle began, even the most severely affected animals re-grew normal hair.

"Once the hair forms," Coulombe explained, "the hair follicle undergoes a developmental cycle throughout its adult life. Hair oscillates between two states - growth and resting. Its conversion from growing to resting occurs periodically with a frequency depending on the type of hair - scalp hair, body hair and so forth. As part of this conversion," he went on, "the hair commits partial suicide. It destroys parts of itself to reach this resting state. That happens through controlled apoptosis. In a mouse, the first of these conversion phases takes place beginning about two weeks after birth. It starts on top of the head and continues in a specially synchronized fashion, toward the mouse's bottom. That is completed maybe a couple of days later over the entire surface of the animal.

"Our K17-null mice started to show the same kind of apoptosis at five days after birth, as opposed to two weeks. These cells were dying in K17-null mice, way earlier than they should - as if to implicate K17 in a cell survival-promoting role. That's where apoptosis acted in the hair-loss phenotype that we saw. Alopecia in K17 KO mice is therefore the result of two phenomena. One of them is the fragility of the hair. The other, this apoptotic cell-death component, a propensity for part of the follicle to die."

What Is K17's Guilty Secret Dividing Mice, Folks?

"Most dermatologists will tell you," Coulombe commented, "that this particular mouse model does not correspond exactly to any specific human baldness condition. Inherited mutations in K17 do cause diseases that involve the hair, but these two disorders are better known for their spectacular involvement at the nails or sebaceous glands. Why is this particular keratin, K17, and none of the other keratins, expressed in hair follicles, so crucial to mouse hair? Why don't we see something as spectacular in the human situation?

"The problem is the two disorders. Human patients are not amenable to biopsies for experimental studies. We cannot, for practical and even ethical reasons, test our idea with these patients that these two diseases are different, even though they might arise from the same keratin genes. We can, though, focus on hair tissue, which is readily accessible at various body sites. You don't have to cut up the skin; you just have to clip the hair. We can ask some questions about the keratin makeup, especially as to K17 and K16.

"One might survey the hair from various individuals in a given race and between races, for instance, to see if there are variations of keratin regulation consistent with the model we're proposing. In that case, we'd probably do testing on hair clippings, to begin with, and subject them to protein extraction and analysis." Coulombe concluded: "We're in the midst of collecting hair-clipping samples from people around us."