title: MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik, Iceland.
authors.forename: Christine
authors.initials: C
authors.lastname: Grill
authors.forename: Kristín
authors.initials: K
authors.lastname: Bergsteinsdóttir
authors.forename: Margrét H
authors.initials: MH
authors.lastname: Ogmundsdóttir
authors.forename: Vivian
authors.initials: V
authors.lastname: Pogenberg
authors.forename: Alexander
authors.initials: A
authors.lastname: Schepsky
authors.forename: Matthias
authors.initials: M
authors.lastname: Wilmanns
authors.forename: Veronique
authors.initials: V
authors.lastname: Pingault
authors.forename: Eiríkur
authors.initials: E
authors.lastname: Steingrímsson
mesh_terms: D000293:Adolescent; D000328:Adult; D016115:Albinism, Oculocutaneous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D003638:Deafness / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014849:Waardenburg Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D051739:Microphthalmia-Associated Transcription Factor