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Xeroderma pigmentosum group B (XP-B) is an autosomal recessive disorder marked by extreme cutaneous photosensitivity and a high predisposition to UV-induced skin cancers. The XPB helicase, encoded by ERCC3 [HGNC:3435], is a core component of the TFIIH complex, which functions in both nucleotide excision repair (NER) and transcription initiation. Pathogenic variants in ERCC3 compromise NER and transcription, leading to the XP-B phenotype.
Several case reports have delineated the genetic basis of XP-B. Three affected individuals have been reported: one unrelated patient (XP11BE) carrying a splice-site variant and a sib-pair (XPCS1BA and XPCS2BA) sharing a missense change c.296T>C (p.Phe99Ser) ([PMID:8304337]) and a consensus frameshift in XP11BE ([PMID:8663148]). This constitutes one sib-pair and one singleton, consistent with autosomal recessive inheritance.
Segregation analysis demonstrated that in the sib-pair family, the variant co-segregated with disease in two affected siblings ([PMID:8304337]). No carriers have been reported to manifest clinical features. The inheritance mode is autosomal recessive, and one additional affected relative confirms segregation.
Functional studies provide robust experimental concordance. Microinjection of wild-type ERCC3 corrected the NER defect in XP-B cells, whereas expression of the mutant p.Phe99Ser or the K436R helicase-dead variant abrogated repair and induced chromatin collapse ([PMID:8304337];[PMID:8157004]). TFIIH complexes isolated from XP11BE cells exhibited reduced 3′→5′ helicase and ATPase activities, leading to defective UV-induced damage incision and decreased transcription initiation in vitro ([PMID:8663148];[PMID:17466626]).
The combined genetic and functional evidence supports a mechanism of hypomorphic loss of ERCC3 helicase function, impairing both global genome NER and transcriptional support of damage recognition. This dual defect explains the XP-B clinical spectrum, including photosensitivity and cancer predisposition without the neurodevelopmental features seen in other TFIIH-related syndromes.
Key Take-home: Biallelic pathogenic variants in ERCC3 underlie XP-B by compromising TFIIH-mediated NER and transcription, guiding molecular diagnosis, carrier testing, and consideration of tailored UV-protection strategies.
Gene–Disease AssociationModerate3 probands (one unrelated and one sib-pair) with biallelic ERCC3 variants, consistent AR inheritance, concordant functional data Genetic EvidenceModerateThree pathogenic variants in three affected individuals and one segregating relative under autosomal recessive model Functional EvidenceStrongMultiple in vivo and in vitro assays demonstrate NER defect correction by wild-type ERCC3 and loss of repair/transcription function for patient variants |