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Identified: Porokeratosis variant caused by silenced gene

Photo courtesy Kobe University

For the first time, researchers have identified epigenetic silencing as the cause of a skin disease—a finding the investigators say could mean other skin diseases may have similar causes.

In a paper published online in The American Journal of Human Genetics (April 22, 2024), the investigators detail that they discovered non-hereditary versions of the clonal keratinization disorder porokeratosis.

They note that previous studies showed that genetic alterations in genes in the mevalonate pathway cause hereditary porokeratosis. The non-hereditary version they discovered is associated with epigenetic silencing—switching off an otherwise intact gene—of FDFT1, another gene in the mevalonate pathway.

In a press release, the researchers explain porokeratosis leads to the development of annular or circular, red and itchy lesions. In some individuals, these develop all over the body, in some localized in lines, and in some only in one or very few spots.

The study’s senior author, Kobe University dermatologist Akiharu Kubo, MD, PhD, previously discovered that patients need “two hits” to one of the four genes that, when damaged, were known to cause the disease.

“We get one set of genes from each of our parents, which means that, for all genes relevant to this disease, we have two copies. However, patients had one deficient copy in all of their cells, which means that they inherited that from one of their parents,” said Dr. Kubo, in the release. “But they also had later mutations in the other copy in those areas of the skin where the disease developed.”

After that discovery, more than fifty patients visited Keio University Hospital in Tokyo and Kobe University Hospital in Kobe, Japan, to get screened by Kubo. Among these, they found eight patients who did not have deficiencies in any of the four genes known to cause the disease, and they also had slightly different symptoms.

“I was convinced that there is a yet unknown cause of porokeratosis, and so my graduate student at Keio University, Saito Sonoko, started to search for it.”

While patients who had lesions all over the body had one deficient copy of FDFT1 inherited from one parent and one later mutation in the affected cells, which is similar to what is known for other causative genes, those with more localized lesions did not have such an inherited damaged copy.

 “These observations led to the hypothesis that not genetic, but epigenetic changes in FDFT1 are hidden as the first hits,” Dr. Kubo said. “And that is exactly what we found. Epigenetic silencing of FDFT1 during early embryonic development in a cell that will give rise to skin cells is the first hit in this type of porokeratosis.”

Dr. Kubo said there are three implications of these findings.

First, identifying the affected gene allows for targeted treatment. Dr. Kubo and his colleagues treated three patients with FDFT1-deficient porokeratosis with atorvastatin, which blocks cholesterol production, and cholesterol ointment. All individuals exhibited reduced skin redness and thickening, itching, and scaling within four to 12 weeks of starting treatment, with no relapse.

Second, it can be reassuring to patients who do not have the inherited form of the disease that they will not pass the predisposition to the illness on to their children.

Third, this is the first skin disease known to be caused by early-development epigenetic silencing of a particular gene. The only other fully comparable mechanism is only known in Lynch syndrome, Dr. Kubo said. “We thus expect that epigenetic causes are hidden not only in these but also in other diseases, suggesting the existence of a category of diseases associated with the silencing of genes.”

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