Lambda Canada | Novel heterozygous mutations of CARD11 as a risk factor for atopic dermatitis
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Novel heterozygous mutations of CARD11 as a risk factor for atopic dermatitis

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Atopic dermatitis is a chronic or recurrent inflammatory skin disease affecting 15-20% children and 1-3% adults worldwide. It is a rare disease in India with prevalence rate of 0.9%. Atopic dermatitis is more prevalent in countries such as UK and New Zealand with the prevalence rate of 25-30%, followed by Europe and Australia with the prevalence rate of 15-20% and 10.7-21% in US.


Immune response observed during atopic dermatitis is characterized by a biphasic inflammation. A T helper type 2 cells (Th2) biased immune response is responsible in the initial and acute phase of disease, whereas in chronic skin lesions, Th1/Th0 are responsible. Latest research published in the journal of ‘Nature Genetics’ by the researchers from National Institute of Allergy and Infectious Diseases (NIAID) – a part of the National Institutes of Health (NIH), explains that mutation of CARD11 is responsible for atopic dermatitis.

Clinical study

Clinical study conducted by NIH-NIAID describes rare hypomorphic dominant-negative mutations in CARD11, which may lead to dominantly inherited severe atopy with variable infections beyond the skin. In this study, eight individuals from four unrelated families were studied for novel heterozygous mutations in CARD11.

Mechanism of gene mutation

CARD11 is a membrane-associated guanylate kinase (MAGUK) family protein that associates with β-cell CLL/lymphoma 10 (BCL10) and lymphoid tissue lymphoma translocation gene 1 (MALT1) genes to form a complex termed as CARD11-BCL10-MALT1 (CBM), which is required for activation of IκB kinase (IKK) and nuclear factor-κB (NF-κB) in response to lymphocyte receptor ligation.


It has been observed that homozygous null mutations in CARD11 results in severe combined immune deficiency (SCID), and heterozygous gain-of-function (GOF) mutations may cause a selective B cell lymphoproliferative disease termed as B cell expansion with NF-κB and T cell anergy (BENTA). Furthermore, CARD11 has also been identified as a risk locus for atopic dermatitis.

Diagnostics of Atopic dermatitis

Elevated level of immunoglobulin E (IgE) along with peripheral blood eosinophilia is suggestive for dominant-negative CARD11 mutations, which could be a common cause of severe allergy in the absence of syndromic features.


In the families with autosomal dominant inheritance with the significant history of atopic dermatitis, heterozygous CARD11 mutations should be considered in genetic testing. Elevated level of IgE and eosinophilia are independent of various other comorbidities.

Presumption by NIAID researcher

Patients of atopic dermatitis had similar T cells defects along with the diminished production of the cytokine interferon-γ (IFN γ). Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor actuated activation of nuclear factor- κB and mammalian target of rapamycin complex 1 (mTORC1).


The defects of mTORC1 and IFN- γ production were partially recovered by supplementation with glutamine, which requires import of CARD11 into T cells. Study findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects which may lead to atopic dermatitis.

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