Mutations in the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia

Previously, nonsense mutations in the gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R) have been described in three patients with severe congenital neutropenia (SCN) (Proc Natl Acad Sci USA 1994; 91: 4480; New Engl J Med 1995; 333: 487). The mutations resulted in the truncation of the carboxy-terminal region of G-CSF-R essential for transduction of maturation signals. Two of these patients developed acute myeloblastic leukemia (AML). We present the results of a search among 20 additional cases of congenital neutropenia (CN) and SCN for the presence of mutations in the cytoplasmic domain of G-CSF-R. This series includes patients with familial and nonfamilial forms of CN and SCN. Mutations in the G-CSF-R gene were found in two new SCN cases. These mutations were nonsense mutations, located in the same cytoplasmic region of G-CSF-R as those found earlier, resulting in the truncation of the C-terminus. Both of these patients developed AML. None of the other patients showed clinical symptoms or cytogenetic features indicative of AML or progression to leukemia. The analysis in this extended series of patients thus has revealed five SCN cases with G-CSF-R mutations, four of whom developed AML. These results add support to the notion that mutations in the G-CSF-R gene, affecting the maturation signaling function of the receptor, define a distinct subgroup of SCN with increased susceptibility to AML.