ERCC6 – UV-sensitive syndrome

UV-sensitive syndrome (UV-sensitive syndrome) is an autosomal recessive photosensitivity disorder characterized by cutaneous photosensitivity (HP:0000992), hyperpigmentation (HP:0000953), and freckling (HP:0001480), resulting from defective transcription-coupled nucleotide excision repair (TC-NER). UVSS comprises three complementation groups: UVSS/CS-A (ERCC8), UVSS/CS-B (ERCC6), and UVSSA. A landmark study classified UVSS/CS-B and established ERCC6 as the causative gene in this group, linking biallelic ERCC6 mutations to the UVSS phenotype ((PMID:22466612)). No additional unrelated probands or specific ERCC6 variants for UVSS have been reported, and segregation data are lacking.

ERCC6 encodes the CSB protein, which remodels stalled transcription complexes at UV-induced DNA lesions to facilitate TC-NER. Loss-of-function of ERCC6 impairs hypophosphorylation of RNA polymerase II after UV exposure, leading to persistent transcription blocks and photosensitivity, consistent with UVSS clinical features. Although functional assays in related transcription-coupled repair disorders demonstrate ERCC6-dependent UV hypersensitivity, direct experimental validation in UVSS/CS-B patients remains to be performed.

Key Take-home: Biallelic ERCC6 mutations underlie the UVSS/CS-B subtype of UV-sensitive syndrome, supporting ERCC6 inclusion in genetic testing panels for UVSS.

References

• Nature genetics • 2012 • Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair. PMID:22466612

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