title: Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases.
abstract: 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 ITK(R29H) 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.
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Centre for Child and Adolescent Health, Medical Faculty, Heinrich-Heine University, Dusseldorf, Germany.
authors.forename: R M
authors.initials: RM
authors.lastname: Linka
authors.forename: S L
authors.initials: SL
authors.lastname: Risse
authors.forename: K
authors.initials: K
authors.lastname: Bienemann
authors.forename: M
authors.initials: M
authors.lastname: Werner
authors.forename: Y
authors.initials: Y
authors.lastname: Linka
authors.forename: F
authors.initials: F
authors.lastname: Krux
authors.forename: C
authors.initials: C
authors.lastname: Synaeve
authors.forename: R
authors.initials: R
authors.lastname: Deenen
authors.forename: S
authors.initials: S
authors.lastname: Ginzel
authors.forename: R
authors.initials: R
authors.lastname: Dvorsky
authors.forename: M
authors.initials: M
authors.lastname: Gombert
authors.forename: A
authors.initials: A
authors.lastname: Halenius
authors.forename: R
authors.initials: R
authors.lastname: Hartig
authors.forename: M
authors.initials: M
authors.lastname: Helminen
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.forename: P
authors.initials: P
authors.lastname: Stepensky
authors.forename: K
authors.initials: K
authors.lastname: Vettenranta
authors.forename: K
authors.initials: K
authors.lastname: Köhrer
authors.forename: M R
authors.initials: MR
authors.lastname: Ahmadian
authors.forename: H-J
authors.initials: HJ
authors.lastname: Laws
authors.forename: B
authors.initials: B
authors.lastname: Fleckenstein
authors.forename: H
authors.initials: H
authors.lastname: Jumaa
authors.forename: S
authors.initials: S
authors.lastname: Latour
authors.forename: B
authors.initials: B
authors.lastname: Schraven
authors.forename: A
authors.initials: A
authors.lastname: Borkhardt
mesh_terms: D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D005260:Female; D018095:Germ-Line Mutation; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000821:virology*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase