Reduced level of the repair/transcription factor TFIIH in trichothiodystrophy
Authors: Tiziana Nardo
Jean-Marc Egly
Alan R Lehmann
Elena Botta
Antonia M Pedrini
Miria Stefanini
Journal: Human molecular genetics (2002)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Trichothiodystrophy; Nucleotide excision repair; TFIIH; Mutations; XPD
Affiliations: Istituto di Genetica Molecolare CNR, via Abbiategrasso, 207, 27100 Pavia, Italy.

Abstract:  Trichothiodystrophy (TTD) is a rare hereditary multisystem disorder associated with defects in nucleotide excision repair (NER) as a consequence of mutations in XPD, XPB or TTDA, three genes that are all related to TFIIH, the multiprotein complex involved in NER and transcription. Here we show that all the mutations found in TTD cases, irrespective of whether they are homozygotes, hemizygotes or compound heterozygotes, cause a substantial and specific reduction (by up to 70%) in the cellular concentration of TFIIH. Intriguingly, the degree of reduction in the level of TFIIH does not correlate with the severity of the pathological phenotype, suggesting that the severity of the clinical features in TTD cannot be related solely to the effects of mutations on the stability of TFIIH. We have also measured TFIIH levels in cells in which different mutations in the XPD gene are associated with clinical symptoms not of TTD but of the highly cancer-prone disorder xeroderma pigmentosum (XP). We have found mild reductions (up to 40%) in TFIIH content in some but not all of these cell strains. We conclude that the severity of the clinical features in TTD patients and the clinical outcome of differentially mutated XPD proteins is likely to depend both on the effects that each mutation has on the stability of TFIIH and on the transcriptional activity of the residual TFIIH complexes. 

Retracted: No

PubPeer comments:
 Copy and pasted from comment on pre-print server: Janet Aisbett 2 months ago u201cThe analysis as presented does not appear to support the conclusion that u201cindividuals discharged from hospital following COVID-19 face elevated rates of multi-organ dysfunctionu2026..u201d. We can conclude that these individuals have elevated rates of multi-organ dysfunction, but we have no way of knowing whether these were u2018new-onsetu2019 events after discharge or were factors contributing to the severity of the individualu2019s COVID episode. This is because u2018new-onsetu2019 events are defined with respect to HES APC and GDPPR extracts over the ten years prior to 2020. It would help if counts of u2018new-onset eventsu2019 were provided, broken into those which first appear in 2020 but before discharge (e.g., as secondary diagnostic codes alongside the COVID primary) and those which first appear post-discharge. Forgive me if I have missed something, but I also have concerns about the 1:1 matching of the COVID cases to controls. Supplementary Table 1 suggests very coarse matching criteria. The use of an age category 70+ is particularly striking, given the comparative age distributions of COVID versus all hospitalisations. The matching of clinical characteristics also deserves further explanation. As presented, it appears that an episode of skin cancer eight years ago could allow a match to an individual with metastasised tumours requiring palliative care. Since more serious comorbidities may be a factor in COVID hospitalisation, matching on coarse clinical characteristics may tend to select a healthier control group. Presenting frequencies of selected sets of ICD-10 codes by age for the COVID cohort versus the control group would help resolve this question. Also worthy of explanation are the decisions not to include dementia in the matched histories, and not to consider previous hospitalisation. Finally, the Supplementary Table 3 shows quite different outcomes for controls matched to ICU COVID cases compared with controls matched to non-ICU cases. These differences are not reflected in the COVID cohort. Although numbers are small for the ICU control group, the discrepancy is worthy of comment.u201d Given the press coverage of this study and promotion by vaccine skeptics on social media, it would be appreciated if the authors could provide some responses to the comment shared above. ,