Trichothiodystrophy causative TFIIEβ mutation affects transcription in highly differentiated tissue

Abstract

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 (NPS-TTD) 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 repair-independent transcription defect and tissue-specific malfunctioning provide novel mechanistic insight into the etiology of TTD.

PADDAS syndrome associated with hair dysplasia caused by a de novo missense variant of PUM1

“…We could hypothesize an involvement of PUM1 in transcription of genes involved in hair differentiation. As hair is a highly differentiated tissue, it is particularly sensitive to transcription modification, and variants in genes affecting transcription are often associated with hair abnormalities (Kosho et al, ; Theil et al, ; Valenzuela et al, , p. 18).…”

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

“…For example, TTD patients carrying mutations in the TTDN1 gene manifest with clinical symptoms associated with the photosensitive TTD disorder but are DNA repair‐proficient and show no signs of photosensitivity or cancer proneness . Recently, it was discovered that a TTD causative TFIIEβ mutation did not affect the GG‐NER or TC‐NER sub‐pathways of NER, uncoupling any defects in transcription from DNA repair in TTD …”

TFIIE orchestrates the recruitment of the TFIIH kinase module at promoter before release during transcription

“…The TFIIEβ/A150P and /D187Y mutations have been recently associated with TTD syndrome 25,26 , which is so far mainly related to TFIIH mutations. The results presented here show that TTD-related mutations within TFIIE and TFIIH have in common (i) decreasing the cellular concentration of these complexes (Fig.…”

“…23,24 . Remarkably, mutations within the TFIIEβ subunit recently have recently been associated with trichothiodystrophy (TTD), an autosomal recessive developmental disorder mainly related to TFIIH mutations (mostly in ERCC2 / XPD gene and few cases in ERCC3/XPB or GFT2H5/p8/TTD-A genes) and characterized by brittle hairs with alternating dark and light (“Tiger tail”) banding with polarized microscopy and low content of sulfur-containing amino acids 25,26 . TFIIE/TTD patients, like TFIIH/TTD patients also have dry, ichthyotic skin, short stature, microcephaly, cerebellar dysfunction, developmental delay, happy engaging personality, attention deficit hyperactivity disorder, and myopia 27 .…”