Rare Disease Report

New Link Found Between A Rare Skin Disease and Beta-HPV

AUGUST 16, 2018
Einav Keet
Researchers from The Rockefeller University recently uncovered the molecular mechanism which causes individuals with a rare skin condition to be susceptible to human papillomavirus (HPV).

Epidermodysplasia verruciformis (EV) is a rare autosomal, recessive genetic skin disorder in which patients develop chronic HPV infection. Symptoms include hyperpigmented or hypopigmented flat wart-like papules, irregular reddish-brown plaques, seborrheic keratosis-like lesions, and pityriasis versicolor-like macules that begin in childhood; these can occur on the trunk, neck, face, hands, and feet. In addition, 30% to 60% of individuals with this condition go on to develop non-melanoma skin cancers, such as squamous cell carcinomas, typically on sun-exposed areas of the body.

Research has linked the disease to mutations in the EVER1 or EVER2 genes on chromosome 17q25, and virus subtypes HPV5 and HPV8—both ß-HPV viruses—are detected in about 80% of cases. Now, in a recent study published in the Journal of Experimental Medicine, a team led by investigators from Rockefeller’s St. Giles Laboratory of Human Genetics of Infectious Diseases detail new findings on the link between EV and HPV.

The study notes that in individuals with the skin disease, HPV infects skin cells called keratinocytes, triggering their proliferation and causing the skin growths associated with the condition. After investigating for a genetic causal factor of the condition, they discovered that in some cases it was associated with mutations in a human gene coding for the protein CIB1, which was strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. 

In addition, the research team found that patients with CIB1 deficiency had symptoms identical to those with EVER1 or EVER2 mutations and that patients with EVER1 or EVER2 mutations also had very low CIB1 levels, suggesting that the 3 proteins interact. Lead author Jean-Laurent Casanova, MD, PhD, noted in a recent news release that in EV patients, HPV takes advantage of lacking cellular defense mechanisms and may compensate for missing proteins. “When people have mutations in CIB1, EVER1 or EVER2, the ß-HPVs can promote the growth of keratinocytes—and can form warts and cancer—because there’s nothing to stop them, even though they are intrinsically defective, lacking E5 and E8,” he said.

In an interview with Rare Disease Report®, Dr. Casanova explains that ß-HPVs are carried by all humans, in their skin, specifically in their keratinocytes. The first contact with the viruses probably takes place in childhood, during contact with other humans. The team’s new findings, he says, may help point investigators in the direction of a genetic therapy for EV.

“They raise the possibility to rescue CIB1 or EVER genes by gene therapy in keratinocytes,” explains Dr. Casanova. “This is a remote possibility. We are not there, obviously. But like with any genetic disease, the identification of the causative gene is necessary, but not sufficient, for gene therapy.”

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