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The purpose of this study was the appraisal of the clinical and functional consequences of germline mutations within the gene for the IL-2 inducible T-cell kinase, ITK. Among patients with Epstein-Barr virus-driven lymphoproliferative disorders (EBV-LPD), negative for mutations in SH2D1A and XIAP (n=46), we identified two patients with R29H or D500T,F501L,M503X mutations, respectively. Human wild-type (wt) ITK, but none of the mutants, was able to rescue defective calcium flux in murine Itk−/− T cells. Pulse-chase experiments showed that ITK mutations lead to varying reductions of protein half-life from 25 to 69% as compared with wt ITK (107 min). The pleckstrin homology domain of wt ITK binds most prominently to phosphatidylinositol monophosphates (PI(3)P, PI(4)P, PI(5)P) and to lesser extend to its double or triple phosphorylated derivates (PIP2, PIP3), interactions which were dramatically reduced in the patient with the ITKR29H mutant. ITK mutations are distributed over the entire protein and include missense, nonsense and indel mutations, reminiscent of the situation in its sister kinase in B cells, Bruton's tyrosine kinase. [ABSTRACT FROM AUTHOR]

The article discusses the ability of a single-nucleotide polymorphism (SNP) in PAX5 leading to an amino-acid change in the octapeptide domain to confer an inherited susceptibility for childhood pre B-acute lymphoblastic leukemia (ALL). It cites the performance of SNP genotyping of leukemic DNA together with germline DNA on the Illumina Human660W-Quadv1 BeadChip. It also notes the germline mutation in combination with loss of heterozygosity of the wt Pax5 allele and loss of the CDKN2A region.