title: Association of paediatric mastocytosis with a polymorphism resulting in an amino acid substitution (M541L) in the transmembrane domain of c-KIT.
abstract: BACKGROUND
  The receptor tyrosine kinase c-KIT plays a key role in normal mast cell development. Point mutations in c-KIT have been associated with sporadic or familial mastocytosis.
  
  
  OBJECTIVE
  Two unrelated pairs of apparently identical twins affected by cutaneous mastocytosis attending the Mastocytosis Clinic at the Royal Children's Hospital, Melbourne, provided an opportunity to assess the possible contribution of c-KIT germline mutations or polymorphisms in this disease.
  
  
  METHODS
  Tissue biopsy, blood and/or buccal swab specimens were collected from 10 children with mastocytosis. To detect germline mutations/polymorphisms in c-KIT, we studied all coding exons by denaturing high pressure liquid chromatography. Exons showing mismatches were examined by direct sequencing. The influence of the substitution identified was further examined by expressing the variant form of c-KIT in factor-dependent FDC-P1 cells.
  
  
  RESULTS
  In both pairs of twins, a heterozygous ATG to CTG transition in codon 541 was observed, resulting in the substitution of a methionine residue in the transmembrane domain by leucine (M541L). In each case, one parent was also heterozygous for this allele. Expression of M541L KIT in FDC-P1 cells enabled them to grow in human KIT ligand (stem cell factor, SCF) but did not confer factor independence. Compared with cells expressing wild-type KIT at a similar level, M541L KIT-expressing cells displayed enhanced growth at low levels of SCF, and heightened sensitivity to the KIT inhibitor, imatinib mesylate.
  
  
  CONCLUSIONS
  The data suggest that the single nucleotide polymorphism resulting in the substitution M541L may predispose to paediatric mastocytosis.
authors.affiliation: School of Biomedical Sciences, The University of Newcastle, Callaghan, New South Wales 2308, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Foster
authors.forename: E
authors.initials: E
authors.lastname: Byrnes
authors.forename: C
authors.initials: C
authors.lastname: Meldrum
authors.forename: R
authors.initials: R
authors.lastname: Griffith
authors.forename: G
authors.initials: G
authors.lastname: Ross
authors.forename: E
authors.initials: E
authors.lastname: Upjohn
authors.forename: A
authors.initials: A
authors.lastname: Braue
authors.forename: R
authors.initials: R
authors.lastname: Scott
authors.forename: G
authors.initials: G
authors.lastname: Varigos
authors.forename: P
authors.initials: P
authors.lastname: Ferrao
authors.forename: L K
authors.initials: LK
authors.lastname: Ashman
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D001549:Benzamides; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D004200:Diseases in Twins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007223:Infant; D008297:Male; D008415:Mastocytosis / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D014430:Twins, Monozygotic
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit