Klin Padiatr 2009; 221 - A70
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

T Telieps 1, K Huck 1, O Feyen 1, T Niehues 2, F Rüschendorf 3, N Hübner 3, HJ Laws 1, S Knapp 4, HH Wacker 5, A Meindl 6, H Jumaa 7, A Borkhardt 1
  • 1Department of Pediatric Oncology, Hematology and Clinical Immunology, Centre for Child and Adolescent Health, Heinrich Heine University, Duesseldorf, Germany
  • 2Centre for Child and Adolescent Health, HELIOS Klinikum Krefeld, Krefeld, Germany
  • 3Max Delbrück Centre for Molecular Medicine (MDC), Berlin-Buch, Germany
  • 4Structural Genomics Consortium, Nuffield Department of Medicine and Department of Clinical Pharmacology, University of Oxford, Headington, Oxford, UK
  • 5Joint Practice for Hematopathology, Kiel, Germany
  • 6Klinikum rechts der Isar, Technische Universität, Munich, Germany
  • 7Molecular Immunology, Max Planck Institute for Immunbiology, Freiburg, Germany

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.