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|Ref Type||Journal Article|
|Authors||Foster R, Byrnes E, Meldrum C, Griffith R, Ross G, Upjohn E, Braue A, Scott R, Varigos G, Ferrao P, Ashman LK|
|Title||Association of paediatric mastocytosis with a polymorphism resulting in an amino acid substitution (M541L) in the transmembrane domain of c-KIT.|
|Journal||The British journal of dermatology|
|Abstract Text||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.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.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.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.The data suggest that the single nucleotide polymorphism resulting in the substitution M541L may predispose to paediatric mastocytosis.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|KIT||M537L||missense||unknown||KIT M537L (corresponds to M541L in the canonical isoform) lies within the transmembrane domain of the Kit protein (PMID: 16226710). M537L (M541L) is a common polymorphism that has been demonstrated to increase proliferation in the presence of ligand compared to wild-type Kit in culture (PMID: 18795925), but is not associated with tumorigenesis in the population (PMID: 16307017, PMID: 21757432) and therefore, its effect on Kit protein function is unknown.|
|KIT||M541L||missense||unknown||KIT M541L lies within the transmembrane domain of the Kit protein (PMID: 16226710). M541L is a common polymorphism that has been demonstrated to increase proliferation in the presence of ligand compared to wild-type Kit in culture (PMID: 18795925), but is not associated with tumorigenesis in the population (PMID: 16307017, PMID: 21757432), and therefore, its effect on Kit protein function is unknown.|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|KIT M541L||chronic leukemia||sensitive||Imatinib||Phase I||Actionable||In Phase I trials, KIT M541L has been associated with response to Gleevec (imatinib) in chronic eosinophilic leukemia, NOS (PMID: 25015329) and mastocytosis (PMID: 18795925).||25015329 18795925|