Inherited mutations in a single gene may contribute to a severe form of atopic dermatitis (AD), a study of eight patients showed.

Investigators from the National Institute of Allergy and Infectious Diseases (NIAID) and elsewhere identified eight individuals with severe AD from four unrelated families. All of the patients had a mutation in the CARD11 gene, which is part of the nuclear factor–kappa B (NF-kB) pathway.

The patients carried a mutation in just one copy of the gene, while the remaining copy was normal, which was a surprise given the severity of the disease (Nat Genet. 2017 Jun 19. doi: 10.1038/ng.3898 ). “You would expect to have a mutation on both alleles, not just one,” in patients with such severe disease, said Josh D. Milner, MD , one of the senior authors and chief of the genetics and pathogenesis of allergy section in the NIAID’s Laboratory of Allergic Diseases.

When the mutated genes were inserted into T cells, the researchers found that the mutated copy of the gene interfered with the normal copy, preventing the activation of NF-kB and mTORC1 (mammalian target of rapamycin complex 1) – effects that may contribute to the severity of AD in these patients.

The results could have broad-ranging clinical implications, Dr. Milner said in an interview. CARD11 has been shown to be associated with AD in previous genomewide association studies. “It may not be the case that this is just found in a few rare families. This could potentially be a gene or pathway that could explain a lot of atopic dermatitis,” he noted.

The study results also point to a potential therapy for AD. The pathway can lead to a deficiency in glutamine uptake into cells, and the study suggests that glutamine supplementation could potentially restore some cells to normal functioning.

Dr. Milner also pointed out that glutamine deficiency could be an indirect consequence of the disease. “Kids with bad allergic disease are usually on a poor diet because they are avoiding foods. They may not be getting enough protein intake,” he said.

In fact, a prevention trial in premature infants sought to determine if glutamine supplementation could reduce infections. The primary endpoint failed, but researchers noted a reduction in AD, according to Dr. Milner. “That’s pretty amazing, given what we just found.”

This study is among recent studies that have highlighted potential targets for treatment of AD, including one reporting that tumor necrosis factor–like weak inducer of apoptosis, a protein, may be involved in both AD and psoriasis ( Nat Commun. 2017 May 22;8:15395. ).

Research identifying novel pathways involved in AD led to the development of dupilumab, which targets interleukin-4 and interleukin-13 and was recently approved by the Food and Drug Administration for moderate to severe AD. It is the first targeted biologic therapy to become available for AD. “I can’t underscore the importance of dupilumab enough,” Dr. Milner commented.

He and the other authors had no related disclosures.


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