Association of paediatric mastocytosis with a polymorphism resulting in an amino acid substitution (M541L) in the transmembrane domain of c-KIT
R. Foster
School of Biomedical Sciences
Hunter Medical Research Institute
Search for more papers by this authorE. Byrnes
School of Biomedical Sciences
Hunter Medical Research Institute
Search for more papers by this authorC. Meldrum
Hunter Medical Research Institute
Medical Genetics, John Hunter Hospital, Newcastle, NSW, Australia
Search for more papers by this authorR. Griffith
Hunter Medical Research Institute
School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia
Search for more papers by this authorG. Ross
Department of Dermatology, Royal Children’s Hospital, Parkville, Vic., Australia
Search for more papers by this authorE. Upjohn
Department of Dermatology, Royal Children’s Hospital, Parkville, Vic., Australia
Search for more papers by this authorA. Braue
Department of Dermatology, Royal Children’s Hospital, Parkville, Vic., Australia
Search for more papers by this authorR. Scott
School of Biomedical Sciences
Hunter Medical Research Institute
Medical Genetics, John Hunter Hospital, Newcastle, NSW, Australia
Search for more papers by this authorG. Varigos
Department of Dermatology, Royal Children’s Hospital, Parkville, Vic., Australia
Search for more papers by this authorP. Ferrao
School of Biomedical Sciences
Hunter Medical Research Institute
Search for more papers by this authorL.K. Ashman
School of Biomedical Sciences
Hunter Medical Research Institute
Search for more papers by this authorR. Foster
School of Biomedical Sciences
Hunter Medical Research Institute
Search for more papers by this authorE. Byrnes
School of Biomedical Sciences
Hunter Medical Research Institute
Search for more papers by this authorC. Meldrum
Hunter Medical Research Institute
Medical Genetics, John Hunter Hospital, Newcastle, NSW, Australia
Search for more papers by this authorR. Griffith
Hunter Medical Research Institute
School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia
Search for more papers by this authorG. Ross
Department of Dermatology, Royal Children’s Hospital, Parkville, Vic., Australia
Search for more papers by this authorE. Upjohn
Department of Dermatology, Royal Children’s Hospital, Parkville, Vic., Australia
Search for more papers by this authorA. Braue
Department of Dermatology, Royal Children’s Hospital, Parkville, Vic., Australia
Search for more papers by this authorR. Scott
School of Biomedical Sciences
Hunter Medical Research Institute
Medical Genetics, John Hunter Hospital, Newcastle, NSW, Australia
Search for more papers by this authorG. Varigos
Department of Dermatology, Royal Children’s Hospital, Parkville, Vic., Australia
Search for more papers by this authorP. Ferrao
School of Biomedical Sciences
Hunter Medical Research Institute
Search for more papers by this authorL.K. Ashman
School of Biomedical Sciences
Hunter Medical Research Institute
Search for more papers by this authorConflicts of interestNone declared.
P.F. (present address: Peter MacCallum Cancer Institute, Melbourne, Vic., Australia) and L.K.A. are joint senior authors.
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.
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