Methods: To identify the cause of Combined Immunodeficiency in 2 patients from 2 different consanguineous Qatari families who had a similar clinical and immunologic phenotype, we used whole-exome sequencing. The patients presented at an early age with fungal, viral and bacterial infections. The patients had hypogammaglobulinemia, normal numbers of B and T cells (most of which were CD45RA positive) and low numbers of NK cells. T cell proliferative responses to mitogens were normal, but were absent to antigens and anti-CD3. We looked for homozygous variants that were present in the patients but absent in controls and public databases. Additional studies included IKKβ, IKBα, and phospho-IKBα immunoblotting, retroviral mediated reconstitution of IKKβ, and cell growth in an immortalized patient B cell line.
Results: We found the same homozygous nonsense mutation in IKBKB (R286X) in both patients. IKKβ acts as part of the IKK complex in NF-κB activation and phosphorylates the NF-κB inhibitor, IKBα. The mutation co-segregated with disease in both families. Western blotting showed absence of detectable IKKβ, and retroviral mediated reconstitution with wild type IKKβ corrected cell growth and restored IKBα phosphorylation and IKBα degradation in an EBV transformed patient B cell line.
Conclusion: These data indicate that mutated IKBKB is the likely cause of immunodeficiency in these two patients. To our knowledge, this is the first report of combined immunodeficiency caused by a mutation in IKBKB.