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

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MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. / Grill, Christine; Bergsteinsdóttir, Kristín; Ogmundsdóttir, Margrét H; Pogenberg, Vivian; Schepsky, Alexander; Wilmanns, Matthias; Pingault, Veronique; Steingrímsson, Eiríkur.

In: HUM MOL GENET, Vol. 22, No. 21, 01.11.2013, p. 4357-67.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Grill, C, Bergsteinsdóttir, K, Ogmundsdóttir, MH, Pogenberg, V, Schepsky, A, Wilmanns, M, Pingault, V & Steingrímsson, E 2013, 'MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function', HUM MOL GENET, vol. 22, no. 21, pp. 4357-67. https://doi.org/10.1093/hmg/ddt285

APA

Grill, C., Bergsteinsdóttir, K., Ogmundsdóttir, M. H., Pogenberg, V., Schepsky, A., Wilmanns, M., Pingault, V., & Steingrímsson, E. (2013). MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. HUM MOL GENET, 22(21), 4357-67. https://doi.org/10.1093/hmg/ddt285

Vancouver

Grill C, Bergsteinsdóttir K, Ogmundsdóttir MH, Pogenberg V, Schepsky A, Wilmanns M et al. MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. HUM MOL GENET. 2013 Nov 1;22(21):4357-67. https://doi.org/10.1093/hmg/ddt285

Bibtex

@article{4077776da6b34d2fb3df81539980b231,
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. ",
keywords = "Adolescent, Adult, Albinism, Oculocutaneous/genetics, Binding Sites, Child, Child, Preschool, Deafness/genetics, Female, Genetic Variation, HEK293 Cells, Humans, Male, Melanoma/genetics, Microphthalmia-Associated Transcription Factor/genetics, Mutation, Missense, Promoter Regions, Genetic, Transcriptional Activation, Transfection, Waardenburg Syndrome/genetics, Young Adult",
author = "Christine Grill and Krist{\'i}n Bergsteinsd{\'o}ttir and Ogmundsd{\'o}ttir, {Margr{\'e}t H} and Vivian Pogenberg and Alexander Schepsky and Matthias Wilmanns and Veronique Pingault and Eir{\'i}kur Steingr{\'i}msson",
year = "2013",
month = nov,
day = "1",
doi = "10.1093/hmg/ddt285",
language = "English",
volume = "22",
pages = "4357--67",
journal = "HUM MOL GENET",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "21",

}

RIS

TY - JOUR

T1 - MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function

AU - Grill, Christine

AU - Bergsteinsdóttir, Kristín

AU - Ogmundsdóttir, Margrét H

AU - Pogenberg, Vivian

AU - Schepsky, Alexander

AU - Wilmanns, Matthias

AU - Pingault, Veronique

AU - Steingrímsson, Eiríkur

PY - 2013/11/1

Y1 - 2013/11/1

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Albinism, Oculocutaneous/genetics

KW - Binding Sites

KW - Child

KW - Child, Preschool

KW - Deafness/genetics

KW - Female

KW - Genetic Variation

KW - HEK293 Cells

KW - Humans

KW - Male

KW - Melanoma/genetics

KW - Microphthalmia-Associated Transcription Factor/genetics

KW - Mutation, Missense

KW - Promoter Regions, Genetic

KW - Transcriptional Activation

KW - Transfection

KW - Waardenburg Syndrome/genetics

KW - Young Adult

U2 - 10.1093/hmg/ddt285

DO - 10.1093/hmg/ddt285

M3 - SCORING: Journal article

C2 - 23787126

VL - 22

SP - 4357

EP - 4367

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 21

ER -