Details

Autor(en) / Beteiligte

• Foster, R.
• Byrnes, E.
• Meldrum, C.
• Griffith, R.
• Ross, G.
• Upjohn, E.
• Braue, A.
• Scott, R.
• Varigos, G.
• Ferrao, P.
• Ashman, L.K.

Titel

Association of paediatric mastocytosis with a polymorphism resulting in an amino acid substitution (M541L) in the transmembrane domain of c-KIT

Ist Teil von

• British journal of dermatology (1951), 2008-11, Vol.159 (5), p.1160-1169

Ort / Verlag

Oxford, UK: Blackwell Publishing Ltd

Erscheinungsjahr

2008

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• Summary 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. Objectives  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.