Lack of apparent hematologic abnormalities in human patients with c-kit (stem cell factor receptor) gene mutations.

Considerable attention has recently been paid to the molecular biology, cell biology, and mutations of the mouse Steel (SI) and dominant white spotting (W; c-kit) loci, which respectively encode stem cell (SCF; also referred to as mast cell growth and kit ligand7-9) and its cognate cellular receptor tyrosine kinase.’O Mice with mutations at either of these loci have similar developmental defects of the melanocyte, pre-erythroid, and germ cell lineages. In addition to characteristic pigmentary anomalies (white spotting), affected mice exhibit a hypoplastic macrocytic anemia. Ten of 24 murine W mutant c-kit alleles result in anemia even in the heterozygote, and virtually all W alleles result in profound (often lethal) anemia in the homozygote.11-12 Recently, we have shown that human c-kit gene mutations result in piebaldi~m,’~J~ a well-known autosomal dominant genetic disorder characterized only by white spotting. Human piebaldism was one of the first genetic disorders ever recognized, and has never been associated with anemia. Specifically, hematologic abnormalities were not described in any of 42 unrelated probands with heterozygous piebaldism reported since 1950. Table 1 shows hematologic data of six additional patients with heterozygous piebaldism in whom we have defined specific c-kit gene mutations; all values were within the normal ranges for the respective laboratories. In addition, the hematologic values of a previously reported patient with apparent homozygous autosomal dominant piebaldi~m’~ were also entirely normal (M. Hulten, personal communication, September 1991), although his c-kit genes have not yet been analyzed. The c-kit gene is expressed in human erythroleukemia cell lines,I6 and recombinant human SCF enhances the in vitro proliferative response of cultured human marrow cells to other growth factors, including interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and erythropoietin (EPo).’~ Moreover, c-kit antisense oligonucleotides inhibit both (IL-3 + Epo)and (SCF + Epo)-stimulated human erythroid colony proliferation in vitro.’* All of these data are consistent with a role for c-kit in human erythropoiesis. How, then, might the lack of apparent hematologic abnormalities in patients with piebaldism be explained? One trivial possibility is that many mutant human c-kit alleles do result in significant anemia in the heterozygote, but these alleles have just not yet been observed. The two human c-kit frameshifts that we have described14 result in “null” alleles, and thus are