361 Activating KIT mutations are not necessary for mastocytosis

Abstract

Mastocytosis is characterized by increased mast cells in the skin and other tissues. The expression of a KIT activating mutation (predominantly, KIT-D816V) is believed to cause abnormal mast cell growth and the development of mastocytosis. Since this disease is often transient and limited in children, and persistent in adults, we hypothesized that patients with mastocytosis may involve more than KIT mutations. PCR amplicons of the skin lesional c-KIT cDNAs in full-length were obtained from 7 children and 37 adults and subjected to Sanger DNA sequencing analysis. D816V was detected in 69% (24/35) of adults and 44% (4/9) of children. The expression of D816V expression did not correlate with the presence or absence of systemic disease. Activating mutation V560G was identified in adults in 14%, and the known non-activating M541L mutation was found in 14% and 17% of children and adults, respectively. Additional sequence variants resulting from mRNA alternative splicing were 419delE, 502_503insAY and 503_504insYF. These variants were located in the extracellular domain and only detected in children (3/9). No KIT-D816V was detected in 38% of children and 23% of adults. In addition, four adults with mastocytosis only expressed wild type KIT, and two other adults expressed a truncated inactive form of KIT. Our results indicate that posttranscriptional modification of KIT mRNA is associated with childhood-onset mastocytosis and activating KIT mutations other than D816V exist in patients with mastocytosis. Finally, because some patients lack activating KIT mutations or even a functional KIT, it appears other genes are involved in the expression of this disease.