MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function
Standard
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, Jahrgang 22, Nr. 21, 01.11.2013, S. 4357-67.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
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 -