Illustrator Eva Lebens’s two daughters always had unusual hair. In a cartoon she drew about their hair, she showed strangers asking if they could touch it and asking whether it was styled. It was blonde and stiff and frizzy, standing up of its own accord like a mane, and it grew extremely slowly. She got something of an explanation when a dermatologist explained the girls had something called uncombable hair syndrome. They were perfectly healthy; they just had this peculiar nimbus of dandelion fluff. But a more complete explanation arrived last month when a German biologist and her colleagues reported in The American Journal of Human Genetics that they’d unearthed the phenomenon’s cause: mutations in genes involved in the construction of hair itself.
Under the microscope, a normal hair is round and smooth. “Uncombable” hair, however, looks pinched and twisted, sometimes with a groove running along it. The first cases were reported in 1973, and while it eventually became clear that the cause was genetic—it does sometimes run in families—the exact causes were unclear, says Regina Betz, the senior author of the new paper. Betz, who primarily studies hair loss, became interested in the syndrome when a colleague mentioned a UK family with two children with normal hair and two with uncombable hair. He sent her DNA samples from the family, and she and her team sequenced them to see whether they could pick out the gene.
When the gene involved in a genetic condition is unknown, sequencing by itself won’t get you very far. Any person will have hundreds of small differences from most other people and it won’t be clear which difference is the one that matters—unless you have samples from a family in which some members are unaffected. That makes it possible to compare people with shared genetic backgrounds and see which versions of which genes are possessed by those with the disorder. And in the case of this family, Betz and colleagues uncovered a mutation in a gene called PADI3. The children with the syndrome had inherited two copies each of the mutated gene, while their unaffected parents and siblings had at most one copy, which wasn’t enough for them to develop the distinctive hair.
PADI3 encodes an enzyme very familiar to hair researchers: It makes alterations to hair proteins that allow them to be assembled into a shaft. And when the team collected DNA from other people with uncombable hair syndrome, in addition to finding six others with mutations in PADI3, they found two with no PADI3 mutations but with changes in two other genes called TGM and TCHH3. The fact that these three genes in particular are involved in uncombable hair syndrome makes sense, says Betz. “It was already known that all three were working in the same [process] in hair structure,” she says. As it happens, TCHH3 makes the hair protein modified by PADI3, and TGM makes an enzyme that links TCHH3 proteins up. When they go wrong, the hair grows in an odd, twisted pattern. The researchers confirmed it by examining mice without normal PADI3—their fur was also frizzy and looked misshapen under the microscope—and by confirming in cell culture that the enzymes resulting from the mutated genes don’t do what they’re supposed to.
However, there are still many mysteries about uncombable hair. For example, the hair gets notably more controllable and less frizzy with age, usually in adolescence. “We don’t know why it gets better,” says Betz. It’s possible that other proteins that can help compensate for the failure of these three to do their work start to be produced, or that processes involving hormones are somehow involved. Furthermore, there are probably more mutations out there that cause uncombable hair, and it’s possible some involve genes involved in hair structure that will be new to researchers, unlike these three. Betz says that after the paper was published, many parents of kids with the syndrome contacted her, offering to send in their DNA.
In fact, Eva Lebens, who heard about the work from Betz herself, is planning to take part in future studies, along with her daughters. “The hair of the eldest has changed a lot already,” she says, “but the structure is still uncombable!”