Heritable mutations in mastocytosis

While the most well-known mutation associated with SM is the CKIT D816V, there are numerous other mutations that can contribute to mast cell disease and presentation. The CKIT gene produces a tyrosine kinase receptor on the outside of the mast cell. Tyrosine kinases function as switches that turn certain cell functions on and off. When stem cell factor binds to the CKIT receptor, it turns on the signal for the mast cell to live longer than usual and to make more mast cells.

The D816V mutation is located in a specific part of the CKIT gene called exon 17. As many as 44% of SM patients have CKIT mutations outside of exon 17, either alone or in addition to the D816V mutation. (Please note that for the purposes of this post, SM is used to refer to SM, ASM and SM-AHNMD in keeping with the source literature.) Still, most doctors and researchers believe the D816V mutation is not heritable. This has important implications because it means many doctors also believe mast cell disease is sporadic and not heritable.

Almost 75% of MCAD (SM, MCAS, MCL) patients had at least one first degree relative with MCAD. This study, published in 2013, demonstrated that despite the non-heritable nature of the D816V mutation, mast cell disease is indeed heritable. Currently, four heritable mutations present in mast cell patients have been identified.

CKIT is often called KIT. In one family in which the mother, daughter and granddaughter have all have indolent SM, they were all found to have a deletion at position 409 in KIT (called KITdel409.) The KIT F522C mutation has been associated with ISM.   Another heritable mutation, KIT K509I, has been identified multiple times by different researchers. The first publication to identify this mutation was published in 2006. It has been found in a mother/daughter set who have ISM, and in another mother/daughter set in which the mother has ASM and the daughter has CM. This mutation was noted in a 2014 paper to be associated with well differentiated SM.

There have been reports of families in which multiple members with ISM or SM-AHNMD had the D816V mutation. Importantly, in these patients, the mutation was readily found in numerous cell types, including mast cells, CD34+ hematopoietic precursor cells, blood leukocytes, oral epithelial cells, blast cells and erythroid precursors. Despite this finding, the majority of literature continues to report the D816V mutation as not heritable.



G.J. Molderings. The genetic basis of mast cell activation disease – looking through a glass darkly. Critical Reviews in Oncology/Hematology 2014.

G.J. Molderings, B. Haenisch, M. Bogdanow, R. Fimmers, M.M. Nöthen. Familial occurrence of systemic mast cell activation disease. PLoS One, 8 (2013), p. e76241

Hartmann, E. Wardelmann, Y. Ma, S. Merkelbach-Bruse, L.M. Preussenr, C. Woolery, et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology, 129 (2005), pp. 1042–1046

R.A. Speight, A. Nicolle, S.J. Needham, M.W. Verrill, J. Bryon, S. Panter. Rare germline mutation of KIT with imatinib-resistant multiple GI stromal tumors and mastocytosis. J Clin Oncol, 31 (2013), pp. e245–e247

de Melo Campos, J.A. Machado-Neto, A.S.S. Duarte, R. Scopim-Ribeiro, F.F. de Carvalho Barra, J.Vassallo, et al.Familial mastocytosis: identification of KIT K509I mutation and its in vitro sensitivity to imatinib, dasatinib and PK412. Blood, 122 (2013), p. 5267

L.Y. Zhang, M.L. Smith, B. Schultheis, J. Fitzgibbon, T.A. Lister, J.V. Melo, et al. A novel K5091 mutation of KIT identified in familial mastocytosis – in vitro and in vivo responsiveness to imatinib therapy. Leukemia Res, 30 (2006), pp. 373–378

E.C. Chan, Y. Bai, A.S. Kirshenbaum, E.R. Fischer, O. Simakova, G. Bandara, et al. Mastocytosis associated with a rare germline KIT K509I mutation displays a well-differentiated mast cell phenotype. J Allergy Clin Immunol, 134 (2014), pp. 178–187

Akin, G. Fumo, A.S. Yavuz, P.E. Lipsky, L. Neckers, D.D. Metcalfe. A novel form of mastocytosis associated with a transmembrane c- Kit mutation and response to imatinib. Blood, 103 (2004), pp. 3222–3225

Escribano, R. Nunez-Lopez, M. Jara, A. Garcia-Montero, A. Prados, C. Teodosio, et al. Indolent systemic mastocytosis with germline D816 V somatic c-kit mutation evolving to an acute myeloid leukemia. J Allery Clin Immunol, 117 (Suppl.) (2006), p. S125

2 Responses

  1. Sandy January 3, 2015 / 8:29 pm

    Thank you for researching and writing this! So many unknowns… and yet so much that is KNOWN!!!!

  2. Yvonne January 4, 2015 / 1:30 pm

    thanks for this post. Although not formally diagnosed. It seems to me that my grandmother, mother, myself and my daughter all have mast cell activation disease. I hope one day a blood test will find the mutations and that will help with the diagnosis. Maybe one day….

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