Submission Details

KIT gene (21 exons) encodes the 145 kDa receptor tyrosine kinase c-KIT with an extracellular domain, a juxtamembrane domain, tyrosine kinase domain I and tyrosine kinase domain II. c-KIT is maintained in an inactive form through auto-inhibition of the kinase domain. The binding of Stem cell factor (SCF), a KIT ligand, promotes dimerization of the enzyme, ATP binding to the tyrosine kinase domain and auto phosphorylation of the tyrosine residue in the juxtamembrane domain . This process activates downstream pathways. Most of the KIT germline variants are gain of function (GoF), which cause autonomous kinase activation in the absence of ligand SCF binding. Genetics evidences recorded here are from unrelated families (Germany, Japan, France, Belgium and Italy) with variants cosegregating with GIST. Majority of the variants are missense or in frame deletions. Functional studies showed autonomous kinase activation both in cell cultures and nude mice. Imatinib can inhibit the autonomous phosphorylation and achieved long term partial response or stable disease in treated patients. LOD scores from two large families, that had enough affected and unaffected individuals tested and proved cosegregation in at least 3 generations are counted in this curation. Mouse knock in models of corresponding human mutations KIT Asp820Tyr, Val559del and Lys641Glu result in similar phenotypes consistent with KIT GoF mutations. The definitive role of KIT gene in GISTs had been replicated in many genetic and functional studies over time.