A new genotype associated with abnormal NFκB function in immunodeficiency without ectodermal dyplasia

A scaffolding protein, NEMO, associated with a complex required in the NFκB translocation pathway has been previously associated with ectodermal dysplasia-associated immune deficiency (EDID) syndrome. The syndrome is X-linked, and presents clinically as a history of recurrent infections, hypogammaglobulinemia, and poor memory B cell function. Affected individuals have abnormalities of ectoderm-derived tissues, such as hair, skin, nails, and teeth. NEMO, in complex with inhibitor of NFκB kinase (IKK) proteins, is necessary for NFκB translocation and gene activation.

This month, Mooster et al. describe a male patient and brother with immunodeficiency, but without ectodermal dysplasia, that was traced to a novel gene mutation in the 5’ untranslated region in the NFκB essential modifier gene (NEMO) gene. They report that TLR-activated production of TNFα and IFNα in peripheral blood is significantly decreased in the index patient, consistent with impaired innate immune response.

The authors find that a G→T mutation in the +1 position of the intron 1B causes destruction of the exon 1B to exon 2 splice in the NEMO gene. Two abnormally sized NEMO mRNAs with intact coding regions are produced, causing inefficient translation that results in inadequate levels of functional NEMO proteins. NEMO mRNA is 4-fold lower and NEMO protein expression is 8-fold lower in the index patient as compared to normal controls. The brother of the index patient is also affected by the same mutation. Their report is the first description of an immunodeficiency that results from decreased levels of functional NEMO protein, rather than functionally impaired protein.

The authors comment that the absence of ectodermal involvement suggests that either normal ectodermal development has a less stringent requirement for NEMO than does immune function, or other NEMO isoforms are able to compensate for the reduction in the 1B isoform.

We asked the authors about the implications of their report:
JACI: In your conclusion, you suggest that clinical work-up of patients presenting with immunodeficiency consistent with EDID, but without ectodermal involvement, should be evaluated for NEMO mRNA and proteins levels, followed by coding analysis. What implications does the characterization of these patients have for their treatment?

Jana Mooster and Douglas McDonald: In patients with immunodeficiency consistent with EDID, but without ectodermal dysplasia or even with a normal NEMO coding sequence, one should consider evaluating NEMO protein levels and NFκB function. Patients with NEMO deficiency but without ectodermal dysplasia can appear clinically similar to patients with common variable immune deficiency. NEMO deficiency, however, is known to cause susceptibility to atypical mycobacterial infections. Thus, identification of a NEMO mutation identifies patients that require monitoring for potential atypical mycobacterial infections.

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