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Gene mutations suggest potential treatment strategy for severe eczema

Relentless flaky, itchy, bumpy, dry skin is a daily issue for people with eczema. Also known as atopic dermatitis, eczema is an inflammatory skin condition. It affects an estimated 30% of the U.S. population, mostly children and adolescents. Severe atopic dermatitis is a less common form of eczema that can be severely debilitating and may also be accompanied by frequent infections and severe immune system defects.

A team of scientists led by Dr. Joshua D. Milner at NIH’s National Institute of Allergy and Infectious Diseases (NIAID), Dr. Erwin Gelfand at National Jewish Health in Denver, Colorado, and Dr. Andrew L. Snow at the Uniformed Services University of the Health Sciences studied the genetics of patients with severe atopic dermatitis. The results appeared online in Nature Genetics on June 19, 2017.

Using whole-exome sequencing, the researchers found mutations in four patients in a gene called CARD11. None of these mutations were previously known. Other affected family members had the mutations as well, for a total of eight patients.

CARD11 is a signaling protein that helps activate immune system cells called T cells. The protein participates in two important signaling pathways in these cells: the NF-κB and mTORC1 pathways. The CARD11 mutations all had similar effects in T cells; they interfered with activation of both pathways. The mutant forms of CARD11 had a dominant effect. This means that they interfered with the pathways even when normal forms of the protein were present.

CARD11 is critical for mTORC1 activation because it helps transport the essential amino acid glutamine into the cell. The researchers thus tested the idea of adding extra glutamine to cells with CARD11 mutations to bypass the effects of the mutations. Adding glutamine to T cells cultured from the patients partially restored mTORC1 signaling and reversed the T cell defects.

“The presence of these mutations in some patients whose only symptoms are eczema and skin infection related to eczema raises the possibility that there may be a genetic explanation for severe atopic dermatitis in some patients,” Milner notes.

The scientists are now planning to assess the effect of supplemental glutamine and leucine, another amino acid that activates mTORC1, in people with severe eczema. “Our findings suggest that something as simple as glutamine supplementation could be beneficial to [people who have severe eczema], with or without CARD11 mutations present,” Snow says.

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