Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis

Human mastocytosis is characterized by increased mast cells. It usually occ urs as a sporadic disease that is often transient and limited in children a nd persistent or progressive in adults. The c-KIT protooncogene encodes KIT , a tyrosine kinase that is the receptor for mast cell growth factor. Becau se mutated KIT can transform cells, we examined c-KIT in skin lesions of 22 patients with sporadic mastocytosis and 3 patients with familial mastocyto sis, All patients with adult sporadic mastocytosis had somatic c-KIT mutati ons in codon 816 causing substitution of valine for aspartate and spontaneo us activation of mast cell growth factor receptor (P = 0.0001). A subset of four pediatric onset cases with clinically unusual disease also had codon 816 activating mutations substituting valine, tyrosine, or phenylalanine fo r aspartate, Typical pediatric patients lacked 816 mutations, but limited s equencing showed three of six had a novel dominant inactivating mutation su bstituting lysine for glutamic acid in position 839, the site of a potentia l salt bridge that is highly conserved in receptor tyrosine kinases. No c-K IT mutations were found in the entire coding region of three patients with familial mastocytosis, We conclude that c-KIT somatic mutations substitutin g valine in position 816 of KIT are characteristic of sporadic adult mastoc ytosis and may cause this disease. Similar mutations causing activation of the mast cell growth factor receptor are found in children apparently at ri sk for extensive or persistent disease. In contrast, typical pediatric mast ocytosis patients lack these mutations and may express inactivating c-KIT m utations. Familial mastocytosis, however, may occur in the absence of c-KIT coding mutations.