On the right, an inking of a Naegeli syndrome patient, which shows an absence of fingerprint. On the left, a normal fingerprint. Courtesy of The American Journal of Human Genetics
Sufferers of two rare congenital diseases—Naegeli syndrome and Dermatopathia Pigmentosa Reticularis (DPR)—have long endured these symptoms without explanation: The plagued cannot sweat, they have thickened palms and soles, and their fingertips are as smooth as porcelain.
The mystery has finally been unraveled.
Researchers at the Technion-Israel Institute of Technology found that the same genetic mutation causes both Naegeli syndrome and DPR. The mutation produces a defect in the protein keratin 14 (KRT14) and causes skin cells to be inappropriately targeted for programmed cell death (or apoptosis).
The finding suggests that the two disorders, which were previously thought to be distinct, might actually be one.
“These two disorders are caused from the mutations located in the same domain of
[the gene KRT14], and we can claim now that they are actually [the] same disease,” said Jennie Lugassy, the lead researcher of the new study, published in the October issue of The American Journal of Human Genetics.
Interestingly, another defect in the same gene is known to cause a third, very different disease. The new finding suggests that there is not just one gene for each genetic disorder.
The most distinctive trait of Naegeli syndrome is that sufferers have absolutely no fingerprints—other characteristics include teeth deformity, nail degeneration, and small brown skin spots that slowly disappear with age. DPR causes most of these symptoms, but also causes lifelong persistence of skin spots and partial hair loss. Both disorders are inherited in an autosomal dominant fashion, where every member of a carrier family exhibits symptoms.
Naegeli syndrome affects only one in every two to four million people, and was first discovered nearly 80 years ago in a large Swiss family. Since then, it and the similarly rare DPR have been identified in four more families—one each in Italy, the U.K., France, and the U.S.
In the late 1980s, a Technion team, led by researchers Gabriele Richard and Peter Itin, began collecting and analyzing DNA samples from 25 members of these five families. Near the turn of the century, advances in gene mapping enabled the researchers to narrow down the location of the responsible gene to a single chromosome.
But it was not until this year that Lugassy finally pinpointed the culprit gene: KRT14.
What surprised Lugassy and her colleagues most was that a mutation in KRT14 had already been linked to another genetic disorder—Epidermolysis Bullosa Simplex (EBS), which doesn’t resemble Naegeli syndrome or DPR.
The symptoms of EBS, which affects one in every 30,000 to 50,000 people, include an exquisite sensitivity to touch: Patients develop painful skin blisters at the slightest chafe, a problem that leads to scarring, disfigurement, and even early death.
The mutations that cause both Naegeli syndrome and DPR lie in a region near the beginning of the KRT14 coding sequence. The mutation that causes EBS in contrast, lies further down the gene.
“If the mutation is located at a certain place it gives you EBS, and if it is located at another place, it gives you another phenotype,” said biologist Eli Sprecher, a co-author of the paper.
The mutations that cause EBS interfere with KRT14’s cytoskeletal role. Instead of forming fine threads, mutated keratins clump together and, Sprecher said, “the cytoskeleton just collapses.”
In Naegeli syndrome and DPR, the mutations seem to prevent KRT14 from playing its normal role in preventing cell death.
Discovering the precise mechanism responsible for the apoptosis could have broad implications, potentially opening up a new window on cancer research.
“Apoptosis is something that is very important in preventing cancer from developing,” Sprecher said. “Here, in contrast, you have inappropriate activation of this program.”
Originally published September 20, 2006