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Gene mutation identified in atopic dermatitis


A new study shows that mutations in the gene CARD11 are associated with severe atopic disease.

Scientists have discovered that a single gene mutation, in the CARD11 gene, could lead to atopic dermatitis. Something as simple as amino acid glutamine supplementation might correct the defect’s cell-signaling misfires, according to a study published August 2017 in Nature Genetics.

Single genes can offer critical insight into why severe immune disorders occur. But few monogenic causes of common allergic diseases, including atopic dermatitis, have been reported. 

The authors of this study looked at gene sequencing in patients with severe atopic dermatitis and identified CARD11 gene mutations in eight patients, from four families. CARD11 encodes the protein of the same name CARD11, a cell-signaling protein. Mutations of the gene can lead to not only severe atopic dermatitis, but also infections beyond the skin, in some cases, the authors report. 

In atopic dermatitis, specifically, the researchers found each of the families had CARD11 mutations that impacted different CARD11 protein domains; yet, all mutations had similar T-cell signaling effects. These different heterozygous hypomorphic CARD11 mutations have the potential to result in severe atopic disease in humans and weaker T cell responses. 

The mutations appear to interfere with activation of two cell-signaling pathways: nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1), which can be activated, in part, by glutamine. 

The researchers went on to find that by growing these patients’ cultured T-cells with excess glutamine, they were able to boost mTORC1 activation, potentially correcting the mutation’s effect on the pathway.

“In essence, it’s entirely possible that severe atopic dermatitis, in the absence of more overt syndromic features, could be caused by a single gene defect. And sometimes that defect might lend to a tailored therapy”, according to study author Joshua Milner, M.D., National Institute of Allergy and Infectious Diseases (NIAID) chief of the Genetics and Pathogenesis of Allergy Section and of the Laboratory of Allergic Diseases.

The study should prompt dermatologists and others who manage atopic dermatitis patients to take note, Dr. Milner says. 

“It certainly raises the question as to whether we should ever be calling bad cases ‘just bad allergy’ or ‘just poorly controlled or controllable atopic dermatitis,’” he says. 

The authors suggest that, in the absence of syndromic features, CARD11 mutations could be a common cause of severe allergy. Dr. Milner and colleagues noted the mutation in not just severe atopic dermatitis, but in a spectrum of atopic disease. 

“Referral bias likely provided us with more severe cases, but some relatives were not as severe and nearly all patients improved over time,” he says. 

Therefore, dermatologists and others should consider looking for heterozygous CARD11 mutations when doing genetic testing for atopic dermatitis in families. 

“[Atopic dermatitis] might have a specific underlying cause, but there may not be clues pointing to any specific syndrome with the possible exception of those who have a dominant inheritance of atopic dermatitis. Perhaps, the index might not have infection but a better history of an infection in the context of atopic dermatitis in immediate relatives might be important to elicit,” Dr. Milner says. 

Genetic screening may have a greater role in common but severe presentations, as more variants like these are found and more is understood about how they work, he says.

While researchers have shown CARD11 is critical for mTORC1 activation, more research is needed to determine which CARD11 domains impact upregulation of ASCT2, an essential glutamine transporter, which leads to mTORC1 engagement. 

Researchers have already started looking at the effects of supplementation with glutamine and leucine to activate mTORC1. 

“We have a protocol about to go to the Institutional Review Board (IRB) to treat moderate-to-severe atopic dermatitis patients with and without CARD11 mutations with glutamine and leucine supplementation. Glutamine supplementation worked to prevent atopic dermatitis in a randomized trial of preterm infants followed out to six years, so we are very enthusiastic that this might have broad implications,” Dr. Milner says.

The simple treatment has the potential to restore mTORC1 signaling in activated T cells, lessening atopic disease in patients with functional CARD11 mutations or related genes, according to the study. 


Chi A Ma, Jeffrey R Stinson, Yuan Zhang, et al. "Germline hypomorphic CARD11 mutations in severe atopic disease," Nature Genetics. Published online June 19, 2017. DOI:10.1038/ng.3898 http://go.nature.com/2xNfkWa


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