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

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 syndr...

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Bibliographic Details
Published in:Human molecular genetics 2013-11, Vol.22 (21), p.4357-4367
Main Authors: Grill, Christine, Bergsteinsdóttir, Kristín, Ogmundsdóttir, Margrét H, Pogenberg, Vivian, Schepsky, Alexander, Wilmanns, Matthias, Pingault, Veronique, Steingrímsson, Eiríkur
Format: Article
Language:English
Subjects:
Adolescent
Adult
Albinism, Oculocutaneous - genetics
Albinism, Oculocutaneous - metabolism
Albinism, Oculocutaneous - pathology
Binding Sites
Biochemistry, biophysics & molecular biology
Biochimie, biophysique & biologie moléculaire
Child
Child, Preschool
Colonies
Deafness - genetics
Deafness - metabolism
Deafness - pathology
Female
General Medicine
Genetic Variation
Genetics
Genetics (clinical)
HEK293 Cells
Humans
Life sciences
Male
Melanoma - genetics
Melanoma - metabolism
Melanoma - pathology
Microphthalmia-Associated Transcription Factor
Microphthalmia-Associated Transcription Factor - genetics
Microphthalmia-Associated Transcription Factor - metabolism
Molecular Biology
Mutation, Missense
Promoter Regions, Genetic
Sciences du vivant
Transcriptional Activation
Transfection
Waardenburg Syndrome - genetics
Waardenburg Syndrome - metabolism
Waardenburg Syndrome - pathology
Young Adult
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Summary: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.
ISSN:0964-6906
1460-2083
1460-2083
DOI:10.1093/hmg/ddt285