MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function.

[oculocutaneous albinism]

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 2 A (WS 2 A ) 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 WS 2 A , TS and melanoma patients . We show that most of the WS 2 A and TS mutations fail to bind DNA and activate expression from melanocyte-specific promoters . Some of the mutations , especially R 203 K and S 298 P , 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 .