KIT – Cutaneous Mastocytosis

KIT encodes a receptor tyrosine kinase critical for mast cell development and function. Cutaneous mastocytosis (CM) is characterized by abnormal accumulation of mast cells in the skin and presents with hyperpigmented macules and urticaria pigmentosa ([HP:0200151]). Activating KIT mutations drive clonal mast cell proliferation in CM and related forms of mastocytosis.

In a familial kindred, a germline missense mutation c.2465A>T (p.Asn822Ile) segregated with CM in a father and two children, with histopathological confirmation and in vitro functional assays demonstrating constitutive KIT phosphorylation, imatinib resistance, and dasatinib sensitivity ([PMID:21689725]).

Somatic KIT D816V mutations are recurrent in adult CM. In 110 patients referred for suspected systemic mastocytosis, highly sensitive ARMS-RT-qPCR detected D816V in 1 cutaneous case and 75 systemic cases, whereas standard RT-PCR/RFLP detected only 47 mutations, highlighting assay sensitivity for low mast cell burden in CM ([PMID:25582384]).

Additional studies report the c-kit Asp816Val (c.2459A>T (p.Asp820Val)) mutation in peripheral CD34+CD117+ precursors of 11 adult CM patients by RT-PCR RFLP, confirming early progenitor involvement across myeloid and lymphoid lineages ([PMID:10706069]). KIT D816V also enhances stem cell factor–dependent chemotaxis of CD117+ precursors, explaining tissue mast cell accumulation in CM ([PMID:11493470]).

Functional assays across multiple models show that kinase‐domain mutations, including p.Asn822Ile and D816V, induce ligand‐independent autophosphorylation, downstream STAT3/Akt activation, and increased proliferation and migration of mast cells and precursors. These gain‐of‐function effects are suppressed by tyrosine kinase inhibitors in vitro, supporting targeted therapy.

Collectively, germline and somatic KIT activating mutations in CM demonstrate a gain‐of‐function mechanism underpinning mast cell hyperplasia. Sensitive molecular assays enable early detection in low‐burden cases and guide precision therapy with kinase inhibitors. Key take‐home: KIT mutation testing is clinically useful for diagnosis, prognosis, and selection of targeted therapy in cutaneous mastocytosis.

References

• Experimental Hematology • 2011 • Novel, activating KIT-N822I mutation in familial cutaneous mastocytosis. PMID:21689725
• Leukemia Research • 2015 • The impact of sensitive KIT D816V detection on recognition of indolent Systemic Mastocytosis. PMID:25582384
• Experimental Hematology • 2000 • Analysis of the surface expression of c-kit and occurrence of the c-kit Asp816Val activating mutation in T cells, B cells, and myelomonocytic cells in patients with mastocytosis. PMID:10706069
• Blood • 2001 • The Kit-activating mutation D816V enhances stem cell factor--dependent chemotaxis. PMID:11493470

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