Two relatively common variations in a gene called KIF3A are responsible for an impaired skin barrier that allows increased water loss from the skin, promoting the development of atopic dermatitis, commonly known as eczema. This finding, from a study led by researchers at Cincinnati Children’s Hospital Medical Center, could lead to genetic tests that empower parents and physicians to take steps to potentially protect vulnerable infants from developing atopic dermatitis and additional allergic diseases.

The study details the genetic and molecular mechanisms at work in atopic dermatitis, a skin condition that affects as many as 20% of all children and is characterized by dry, thickened, and intensely itchy skin, particularly in skin folds. Although eczema usually resolves as children age, many children with disrupted skin barriers go on to develop more severe conditions.

People with eczema are more susceptible to bacterial, viral, and fungal skin infections and frequently develop additional conditions such as asthma and food allergies. In fact, people may experience a cascade of allergic conditions if eczema erodes their skin barriers and exposes their subsurface skin to environmental irritants.

“Our data provide a mechanistic basis for the atopic dermatitis disease susceptibility conferred by KIF3A SNPs rs11740584 and rs2299007 whereby the alternate alleles generate new CpG sites resulting in increased methylation and decreased expression of KIF3A,” the researchers reported. “Skin methylation of the novel CpG sites created by rs11740584 and rs2299007 was associated with increased transepidermal water loss in individuals carrying the risk alleles.”

These details appeared in a Nature Communications article titled, “Disease-associated KIF3A variants alter gene methylation and expression impacting skin barrier and atopic dermatitis risk.” The article also clarifies that KIF3A is a gene that codes for a protein involved in generating signals from the outside to the inside of a cell, part of a complex sensory apparatus.

Previously, scientists had identified an association between two genetic variations in KIF3A and asthma in children who also had eczema. In the new study, the researchers found that these variations, or single nucleotide polymorphisms (SNPs), changed parts of the KIF3A gene to a form that can regulate, through a process called methylation, the rate at which a gene is transcribed into the blueprint for protein production.

The investigators confirmed that skin and nasal-lining cells from people with the KIF3A SNP variants had more methylation and contained fewer blueprints for the protein encoded by KIF3A than cells in which KIF3A lacked the SNPs. In addition, the researchers demonstrated that people with the SNP-created regulating sites had higher levels of water loss from the skin.

This graphical abstract shows how two variations in the gene KIF3A can disrupt the skin barrier, allowing allergens to penetrate deeper layers. [Cincinnati Children’s]

To determine whether lower levels of KIF3A caused atopic dermatitis, the scientists studied mice lacking the mouse version of KIF3A in skin cells. They found that these mice also had increased water loss from the skin due to a dysfunctional skin barrier and were more likely to develop features of atopic dermatitis. The investigators concluded that the presence of either or both of the two SNPs in human KIF3A leads to lower production of the KIF3A protein, promoting dysfunction of the barrier that normally keeps skin well hydrated, thereby increasing the likelihood that a person will develop atopic dermatitis.

The study’s findings could make it easier to identify which children with eczema are most likely to progress to other allergic conditions. This would allow lifestyle interventions and other preventive therapies to be targeted toward high-risk children. The study also suggests a new target for potential treatment.

“Food allergies are rising, and the causes are not entirely clear,” said Gurjit Khurana Hershey, MD, PhD, the senior corresponding author of the current study and director of the division of asthma research at Cincinnati Children’s. “This study adds evidence to a rising theory that skin health is more closely connected to lung and gut health than many have suspected.”

Hershey and colleagues also emphasized that proper function of the KIF3A gene is important because it helps cells form their primary cilia, a structure on cell surfaces that acts as an antenna to receive important signal information from other cells.

Previous studies led by experts at Cincinnati Children’s and other institutions have already shown that malfunctions due to adverse KIF3A variants in lung tissue can lead to asthma. Likewise, malfunctions of the same gene in gut tissues can increase risk of food allergies. The current study helps connect both allergy risks to a damaged skin barrier, which allows more allergy-triggering substances to get inside our bodies to prompt immune system overreactions.

“We are working to better understand how skin, gut, and lung health are connected,” Hershey noted. “In fact, we have a grant from the National Institutes of Health to further study this connection.”

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