The transcription factor onecut-2 controls the Microphthalmia-associated transcription factor gene

Microphthalmia-associated transcription factor (MITF) is essential for mela nocyte differentiation. MITF mutations are associated with some cases of Wa ardenburg syndrome (WS) type 2. WS is a dominantly inherited disease charac terized by auditory-pigmentary defects that result from the absence of mela nocytes. The lack of mutation in MITF coding sequences in some WS2 patients suggests that unidentified factors controlling MITF expression might be in volved. We show here that the cut-homeodomain transcription factor Onecut-2 (OC-2) is expressed in melanocytes and binds to the MITF gene promoter. Ov erexpression of OC-2 in transfected cells stimulates MITF promoter activity . Mutations that prevent OC-2 binding decrease MITF promoter activity by 75 %. Based on these results, we searched in 56 WS2 patients for mutations in the OC2 gene or in OC-2 binding sites in the MITF promoter, but none was fo und. These results show that OC-2 stimulates MITF expression and that OC2 i s a candidate gene, but not a common cause, of WS. (C) 2001 Academic Press.