TY - JOUR
T1 - Trichothiodystrophy causative TFIIEβ mutation affects transcription in highly differentiated tissue
AU - Theil, Arjan F.
AU - Mandemaker, Imke K.
AU - van den Akker, Emile
AU - Swagemakers, Sigrid M.A.
AU - Raams, Anja
AU - Wüst, Tatjana
AU - Marteijn, Jurgen A.
AU - Giltay, Jacques C.
AU - Colombijn, Richard M.
AU - Moog, Ute
AU - Kotzaeridou, Urania
AU - Ghazvini, Mehrnaz
AU - von Lindern, Marieke
AU - Hoeijmakers, Jan H.J.
AU - Jaspers, Nicolaas G.J.
AU - van der Spek, Peter J.
AU - Vermeulen, Wim
N1 - Publisher Copyright:
© The Author 2017. Published by Oxford University Press. All rights reserved.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - The rare recessive developmental disorder Trichothiodystrophy (TTD) is characterized by brittle hair and nails. Patients also present a variable set of poorly explained additional clinical features, including ichthyosis, impaired intelligence, developmental delay and anemia. About half of TTD patients are photosensitive due to inherited defects in the DNA repair and transcription factor II H (TFIIH). The pathophysiological contributions of unrepaired DNA lesions and impaired transcription have not been dissected yet. Here, we functionally characterize the consequence of a homozygous missense mutation in the general transcription factor II E, subunit 2 (GTF2E2/TFIIEβ) of two unrelated non-photosensitive TTD (NPSTTD) families. We demonstrate that mutant TFIIEβ strongly reduces the total amount of the entire TFIIE complex, with a remarkable temperature-sensitive transcription defect, which strikingly correlates with the phenotypic aggravation of key clinical symptoms after episodes of high fever. We performed induced pluripotent stem (iPS) cell reprogramming of patient fibroblasts followed by in vitro erythroid differentiation to translate the intriguing molecular defect to phenotypic expression in relevant tissue, to disclose the molecular basis for some specific TTD features. We observed a clear hematopoietic defect during late-stage differentiation associated with hemoglobin subunit imbalance. These new findings of a DNA repairindependent transcription defect and tissue-specific malfunctioning provide novel mechanistic insight into the etiology of TTD.
AB - The rare recessive developmental disorder Trichothiodystrophy (TTD) is characterized by brittle hair and nails. Patients also present a variable set of poorly explained additional clinical features, including ichthyosis, impaired intelligence, developmental delay and anemia. About half of TTD patients are photosensitive due to inherited defects in the DNA repair and transcription factor II H (TFIIH). The pathophysiological contributions of unrepaired DNA lesions and impaired transcription have not been dissected yet. Here, we functionally characterize the consequence of a homozygous missense mutation in the general transcription factor II E, subunit 2 (GTF2E2/TFIIEβ) of two unrelated non-photosensitive TTD (NPSTTD) families. We demonstrate that mutant TFIIEβ strongly reduces the total amount of the entire TFIIE complex, with a remarkable temperature-sensitive transcription defect, which strikingly correlates with the phenotypic aggravation of key clinical symptoms after episodes of high fever. We performed induced pluripotent stem (iPS) cell reprogramming of patient fibroblasts followed by in vitro erythroid differentiation to translate the intriguing molecular defect to phenotypic expression in relevant tissue, to disclose the molecular basis for some specific TTD features. We observed a clear hematopoietic defect during late-stage differentiation associated with hemoglobin subunit imbalance. These new findings of a DNA repairindependent transcription defect and tissue-specific malfunctioning provide novel mechanistic insight into the etiology of TTD.
UR - http://www.scopus.com/inward/record.url?scp=85042234620&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddx351
DO - 10.1093/hmg/ddx351
M3 - Article
C2 - 28973399
AN - SCOPUS:85042234620
SN - 0964-6906
VL - 26
SP - 4689
EP - 4698
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 23
ER -