Preprint: mechanism-selective deep mutational scanning distinguishes ERCC2 disease phenotypes at residue level
A yeast-complementation deep mutational scan of nearly all XPD amino acid substitutions separates ERCC2 variants that disrupt nucleotide excision repair from those that disrupt transcription, offering a functional framework for interpreting pathogenic variants in xeroderma pigmentosum and trichothiodystrophy.
Researchers have posted a preprint to bioRxiv describing a mechanism-selective deep mutational scanning study of ERCC2, the gene encoding the XPD subunit of the general transcription and DNA repair factor TFIIH. Pathogenic ERCC2 variants cause at least two clinically distinct disorders — xeroderma pigmentosum (XP), characterised by extreme UV sensitivity and elevated skin cancer risk, and trichothiodystrophy (TTD), a multisystem developmental syndrome — as well as combinations of features from both. The mechanistic basis for this clinical divergence has remained incompletely understood.
The study used yeast complementation assays to measure the functional consequences of nearly every possible single amino acid substitution across XPD. Critically, the assay was designed to be mechanism-selective: it preferentially reports on the transcription-associated function of XPD rather than its DNA repair role, with pronounced sensitivity to variants at the p44 interface. This design allows individual variants to be assigned to disruption of one or both TFIIH functions, rather than producing a single aggregate pathogenicity score.
The authors argue that this functional separation can help reclassify variants of uncertain significance (VUS) in ERCC2 and may explain why different variant classes produce phenotypically divergent disease. The approach could serve as a template for mechanism-selective functional characterisation of other multi-disease genes. The preprint has not yet undergone peer review. Full author and institutional details are available at the bioRxiv record.
Plain-language version
For patients, families, and general readers. Educational only — not medical advice.
ERCC2 is a gene that plays two important roles in the body: helping to repair damage to DNA caused by ultraviolet light, and helping cells to read the instructions encoded in DNA. Faults in this gene can cause two different inherited conditions — xeroderma pigmentosum, which causes very high sensitivity to sunlight and a raised risk of skin cancer, and trichothiodystrophy, which affects development in multiple ways. Researchers have now used a large-scale laboratory technique to test almost every possible change that could occur in this gene and to work out which of the two cellular functions each change disrupts. The findings could help scientists better categorise genetic changes in ERCC2 that are currently difficult to interpret, including those sometimes described as 'variants of uncertain significance'. This work is at an early stage and has not yet been checked by independent scientific reviewers. This is an educational summary, not medical advice. If anything here raises questions for you, please speak with your GP or a clinical professional.
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Primary sourcePreprint bioRxiv (Cold Spring Harbor Laboratory) · 2026-09-27Mechanism-selective deep mutational scanning distinguishes ERCC2 disease phenotypes