The basic-helix-loop-helix-leucine zipper (bHLHZip) protein MITF 
(microphthalmia-associated transcription factor) is a master regulator of 
melanocyte development. Mutations in the MITF have been found in patients with 
the dominantly inherited hypopigmentation and deafness syndromes Waardenburg 
syndrome type 2A (WS2A) and Tietz syndrome (TS). Additionally, both somatic and 
germline mutations have been found in MITF in melanoma patients. Here, we 
characterize the DNA-binding and transcription activation properties of 24 MITF 
mutations found in WS2A, TS and melanoma patients. We show that most of the WS2A 
and TS mutations fail to bind DNA and activate expression from 
melanocyte-specific promoters. Some of the mutations, especially R203K and 
S298P, exhibit normal activity and may represent neutral variants. Mutations 
found in melanomas showed normal DNA-binding and minor variations in 
transcription activation properties; some showed increased potential to form 
colonies. Our results provide molecular insights into how mutations in a single 
gene can lead to such different phenotypes.