While the exact biological processes that cause atopic dermatitis (AD) are unknown, experts know that a combination of environmental factors, genetic predisposition, and dysfunctions in the immune system and in the barrier of the skin all play a part. Now, researchers have uncovered a new genetic clue that leads to the development of AD.
Researching genetic mutations
Scientists from the National Institute of Allergy and Infectious Diseases (NIAID) discovered mutations in a gene called CARD11 contribute to AD. After studying genetic sequences of people with severe AD, the researchers found CARD11 mutations in eight individuals from four unrelated families. The mutations are germline mutations, meaning they are inherited, passed down from one generation to the next.1,2 CARD11 provides instructions for a protein of the same name, and although the different families in the study had unique mutations, each of the mutations had an effect on the signaling of T-cells. T-cells are a specialized type of white blood cell that are involved in inflammation and are known to play a role in AD.
Conducting the research
With laboratory experiments, the research team determined that the mutations in CARD11 led to defective signaling of T-cells along two pathways. One of these pathways is typically activated by glutamine, an amino acid. When the researchers grew cultured T-cells from patients with the CARD11 mutations that had excess glutamine, they found that the mTORC1 (mechanistic target of rapamycin complex 1) pathway was activated. The mTORC1 pathway plays a role in the normal cellular functions and growth. The research suggests that there may be a potential to correct the signaling defects in people with CARD11 mutations.1,2
This research provides an exciting new discovery on the development of AD as well as a potential way to impact the disease. Next, the researchers plan to study the effect of supplemental glutamine and leucine, another amino acid that plays a role in mTORC1, in people with AD. The supplements will be given to those with known CARD11 mutations as well as some people with AD who do not have CARD11 mutations.1,2
What other genetic factors involved?
The CARD11 mutations are only one of the genetic factors that have been identified as contributing to the development of AD. Another known mutation that is associated with AD is in the gene FLG. Researchers have identified more than 40 mutations in the FLG gene that are associated with up to 50% of patients with moderate to severe AD. However, not all people with FLG mutations develop AD, in addition, not all patients with AD have FLG mutations. While FLG was the first identified and most well-studied gene related to AD, researchers are working to identify additional genes that contribute to the development of the condition.3
National Institutes of Health. Accessed online on 8/7/17 at https://www.nih.gov/news-events/news-releases/scientists-identify-single-gene-mutations-lead-atopic-dermatitis.
CA Ma, JR Stinson, Y Zhang et al. Germline hypomorphic CARD11 mutations in severe atopic disease. Nature Genetics. 2017 Aug;49(8):1192-1201. doi: 10.1038/ng.3898.
Tollefson MM, Bruckner AL. Atopic dermatitis: skin-directed management. Am Acad Pediatrics. 2014 Dec;134(6):e1735-1744. doi: 10.1542/peds.2014-2812.