Systemic Mastocytosis : KIT Mutations
Image Description
KIT Mutations in Systemic Mastocytosis: KIT protooncogene on chromosome 4q12 codes for one of the receptor tyrosine kinases which play a key role in signal transduction following activation by stem cell factor binding. Activating point mutations in KIT are commonly seen in mastocytosis. The majority of these affect codon 816, resulting in substitution of valine for aspartic acid (D816V). This specific mutation is seen in >95% of cases of systemic mastocytosis and about one-third of patients with cutaneous mastocytosis.
Most mutations are detected in exons 11 and 17. Uncommonly, they involve exons 8, 9, and 10. Other KIT codon 816 mutations (D816Y, D816H, and D816F) are rare and occur more frequently in cutaneous mastocytosis than systemic mastocytosis.
The end-result of these mutations is stem cell factor independent activation of KIT which influences downstream signaling pathways leading to enhanced growth and survival of mast cells.
Besides mastocytosis, KIT mutations are also found in piebaldism (white patches of hair and skin caused by lack of melanocytes), gastrointestinal stromal tumor, some cases of acute myeloid leukemia, sinonasal NK/T-cell lymphoma, and seminoma.
About this Image: The image shows structure of the KIT receptor with known function of its domains and localization of all reported KIT mutations in adult patients with mastocytosis. On the left is shown the structure of the receptor. In the center, the 21 KIT exons and the most frequently identified mutations are reported. Abbreviations: Del, deletion; ECD, extracellular domain; Ins, insertion; ITD, internal tandem duplication; JMD, juxtamembrane domain; TKD, tyrosine kinase domain; PTD, phosphotransferase domain; TMD, transmembrane domain. *: mutation found in around 30% of pediatric patients and in > 80% of all adult patients.
Image source: Martelli, M. et al. Recent Advances in the Molecular Biology of Systemic Mastocytosis: Implications for Diagnosis, Prognosis, and Therapy. Int. J. Mol. Sci. 2020, 21(11), 3987; https://doi.org/10.3390/ijms21113987; Used under Creative Commons Attribution (CC BY) License
Most mutations are detected in exons 11 and 17. Uncommonly, they involve exons 8, 9, and 10. Other KIT codon 816 mutations (D816Y, D816H, and D816F) are rare and occur more frequently in cutaneous mastocytosis than systemic mastocytosis.
The end-result of these mutations is stem cell factor independent activation of KIT which influences downstream signaling pathways leading to enhanced growth and survival of mast cells.
Besides mastocytosis, KIT mutations are also found in piebaldism (white patches of hair and skin caused by lack of melanocytes), gastrointestinal stromal tumor, some cases of acute myeloid leukemia, sinonasal NK/T-cell lymphoma, and seminoma.
About this Image: The image shows structure of the KIT receptor with known function of its domains and localization of all reported KIT mutations in adult patients with mastocytosis. On the left is shown the structure of the receptor. In the center, the 21 KIT exons and the most frequently identified mutations are reported. Abbreviations: Del, deletion; ECD, extracellular domain; Ins, insertion; ITD, internal tandem duplication; JMD, juxtamembrane domain; TKD, tyrosine kinase domain; PTD, phosphotransferase domain; TMD, transmembrane domain. *: mutation found in around 30% of pediatric patients and in > 80% of all adult patients.
Image source: Martelli, M. et al. Recent Advances in the Molecular Biology of Systemic Mastocytosis: Implications for Diagnosis, Prognosis, and Therapy. Int. J. Mol. Sci. 2020, 21(11), 3987; https://doi.org/10.3390/ijms21113987; Used under Creative Commons Attribution (CC BY) License