ERCC8 – UV-sensitive syndrome

UV-sensitive syndrome (UVSS) is a rare autosomal recessive photosensitivity disorder caused by defects in transcription-coupled nucleotide excision repair. ERCC8, encoding the CSA protein, defines the UVSS/CS-A complementation group, yet no ERCC8 variants have been reported in UVSS cohorts to date; instead, UVSSA mutations have been identified in UVSS-A patients (PMID:22466612, PMID:31421932). Clinical features include cutaneous photosensitivity (HP:0000992), hyperpigmentation (HP:0000953), and freckling (HP:0001480). While ERCC8’s role in transcription-coupled repair is well established, direct case-level evidence for ERCC8 variants in UVSS is lacking, precluding definitive genotype-phenotype correlations.

Mechanistically, CSA forms a complex with USP7 to stabilize ERCC6 and restore RNA polymerase II after UV damage, consistent with a loss-of-function mechanism in TCR. The absence of reported ERCC8 pathogenic alleles in UVSS limits genetic and functional evidence to a theoretical prediction based on complementation grouping. No conflicting data have emerged, but the current evidence supports only a limited clinical validity for ERCC8 in UVSS.

Key take-home: ERCC8 is biochemically essential for TCR and defines the UVSS/CS-A group, but specific pathogenic ERCC8 variants remain to be identified, limiting its present diagnostic utility.

References

• Nature Genetics • 2012 • Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair. PMID:22466612
• Journal of dermatological science • 2019 • UV-sensitive syndrome: Whole exome sequencing identified a nonsense mutation in the gene UVSSA in two consanguineous pedigrees from Pakistan. PMID:31421932

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