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New Monogenic Form of Severe Atopic Dermatitis Described

NEW YORK (GenomeWeb) – A new study suggests rare mutations in a single gene are enough to prompt severe atopic dermatitis — a form of the disease that sometimes manifests itself not only on the skin, but also through infections such as pneumonia, asthma, or abscesses affecting other tissues.

As they described online today in Nature Genetics, researchers from the National Institute of Allergy and Infectious Diseases (NIAID) and elsewhere did exome sequencing on individuals from four families affected by severe atopic dermatitis, narrowing in on four different mutations affecting one copy of the CARD11 gene. Their follow-up experiments in cell lines and mouse models indicated that this alteration interferes with NF-kappaB and mTORC1 pathways in T immune cells, leading to diminished glutamine transport.

"[W]e describe rare hypomorphic dominant-negative mutations in CARD11, in four unrelated families, that lead to dominantly inherited severe atopy with variable infection beyond the skin," co-senior authors Joshua Milner, Andrew Snow, and Erwin Gelfand — researchers affiliated with the NIAID, the Uniformed Services University of the Health Services, and National Jewish Health, respectively — and their co-authors wrote.

Following from past studies that have pointed to allergic disease risk stemming from mutations affecting individual genes, the researchers set out to find new mutations associated with severe atopic dermatitis.

The team started by capturing protein-coding sequences from eight affected individuals in four families that were prone to severe atopic dermatitis with the Life Technologies' Ion Torrent AmpliSeq exome kit. It then sequenced the exomes with Ion Torrent Ion Proton instrument and version three of the Ion PI chip, searching for severe atopic dermatitis-related mutations with the company's read mapping and variant calling software.

The search led to three missense mutations and one in-frame mutation in CARD11 in individuals with atopic dermatitis who also suffered from infections ranging from pneumonia or bacteria to abscesses, food allergies, dentition problems, and other conditions, the researchers reported.

They saw lower-than-usual activation of both the NF-kappaB and mTORC1 pathways in immune stimulated immortalized T cell lines when heterozygous versions the newly detected CARD11 mutations were introduced to the cell lines, along with reduced activation by the wild type version of the gene.

Similar patterns turned up when the team tested cell lines derived directly from the atopic dermatitis patients, while experiments in mouse cell lines and mouse models supported the notion that some of the dominant negative changes associated with the heterozygous CARD11 mutations could be reversed with extra glutamine.

"[O]ur findings suggest that exogenous glutamine could partially correct specific defects in CARD11-mutant T cell responses, including proliferation and IFN-gamma secretion," the authors wrote. They also noted that glutamine supplements have already been proposed and tested for treating allergic conditions in infants with a low birth weight, "with a promising decrease in atopic dermatitis." 

Consequently, the investigators hypothesized that this "simple therapeutic intervention" might also make a difference for individuals who suffer from atopic disease as a result of rare mutations such as those identified in CARD11 that interfere with glutamine uptake and activated T cell signaling through the mTORC1 pathway.