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DOI: 10.1055/s-0029-1222690
Missense mutation in the inducible T-cell kinase (ITK) leading to immunodeficiency and fatal immune dysregulation after EBV infection
Background: In boys fatal immunodeficiencies linked to mutations in SAP or XIAP are known. Here we describe a novel primary immunodeficiency in girls caused by a homozygous mutation in ITK.
Patients/Methods: MNCs/T-cells from 2 sisters of healthy consanguineous parents with severe immunodeficiency and therapy resistant EBV-positive B-cell proliferation after EBV infection. Additionally 293T cells transfected with mutant ITK plasmids were analyzed. We used linkage analysis and DNA Sequencing for detection of mutations, western blot and lymph node staining for detection of protein expression, RT-PCR for quantification of RNA expression and flow cytometry for description of surface markers.
Result: We found a homozygous missense mutation in both patients (C1085T), leading to the substitution of an arginin residiue at position R335W in ITK by tryptophan. The highly conserved residue R335W is located in the BG-loop of the ITK SH2 domain. In transfected 293T cells RNA levels between mutant and wt ITK were similar, protein expression of mutant ITK was weaker than wt. In silico prediction of protein stability revealed severe destabilization of the SH2 domain.
Conclusion: We report a novel primary immunodeficiency, which leads to an XLP-like phenotype in girls, caused by a homozygous mutation in ITK. ITK deficiency leads to fatal inadequate immune response to EBV.