Mechanism Identified in Causing Rare Skin Disease

A mutation that causes the rare skin disease x-linked reticulate pigmentary disorder (XLPDR) has been identified and could lead to the development of targeted therapies.

The POLA1 gene is an enzyme that plays a role in DNA replication and its genetic mutation has been linked to XLPDR.

A study published in Nature Immunology looked to identify the genetic mutation that causes XLPDR through whole-genome sequencing. Researchers discovered that the mutation was actually in a non-coding intron section of DNA, despite prior knowledge suggesting the mutation was in an exon.

“Genes are like beads on a string, with the beads representing exons that are spliced together after the intervening pieces of string, or introns, are clipped out,” said researcher Andrew Zinn, PhD. “Since the majority of known disease-causing mutations affect proteins, geneticists normally are focused on exons. This intron mutation results in aberrant splicing, decreasing POLA1 protein expression.”

Researchers sought to determine how the genetic mutation led to the phenotype of XLPDR, as well as the immunodeficiency and spontaneous inflammation of different organs.

Upon examination, an association between POLA1 deficiency and an immune reaction to the cytoplasm of cells was found.

“When you examine cells of XLPDR patients under the microscope, they look like they are constantly responding to a viral infection,” said research scientist Petro Starokadomskyy. “But in reality, they are not infected with anything. Interestingly, these patients instead get repeated bacterial and fungal infections, particularly in the lungs. It's like their bodies are exhausted by constant antiviral alarms, and so they cannot respond to real threats.”

The study was able to demonstrate that the generation of cytosolic RNA: DNA hybrids modulates the sensitivity of cellular sensors. In patients with XLPDR the levels of cytosolic RNA: DNA are reduced, causing cells to become spontaneously activated and initiating the beginning steps for the eventual development of the disease.

“These patients are both inflamed and immunodeficient at the same time,” Burstein said. “They have a signature of autoinflammation that is very similar to diseases that involve mutations in enzymes of nucleic acid metabolism. Our research revealed a role for this replicative polymerase as a modulator of interferon activation through the generation of RNA: DNA hybrids in the cytoplasm of cells.”

The cause of this state was pinpointed as constant activation of the interferon pathway. The production started with the recognition of foreign nucleic acids, a process where cells are normally able to detect viruses.

Although there are only 14 families known worldwide to have XLPDR, it’s possible that several other individuals could be misdiagnosed.

Tyler Vansyckle, 25, and Spenser Vansyckle, 20, were initially misdiagnosed with cystic fibrosis because of continual lung infections. However, it wasn’t until a dermatologist took note of their unusual skin coloration that they received their correct diagnosis of XLPDR.

It was then that researchers began working with the Vansyckle family to find the genetic cause of the disease, which was a success.

“It felt like a dream,” said Tom Vansyckle. “I called Dr. Zinn the next morning and asked him, 'Is this really real or did I dream that this happened?’”

Although the findings did not result in an immediate cure for XLPDR, Vansyckle finds comfort knowing others have this disease and that the medical understanding of the condition is advancing.

“For years, we thought we were the only ones in the world,” Vansyckle said.

In families with XLPDR, girls can be screened to see if they are carriers of the disease thanks to the discovery of the mutation.

“Finding a way to block or slow the interferon pathway could someday help these patients,” Burstein said.