UVSSA – UV-sensitive syndrome

UV-sensitive syndrome (UVSS; MONDO:0015797) is a rare autosomal recessive disorder characterized by cutaneous photosensitivity, freckling, and hyperpigmentation without increased skin cancer risk. The causative gene, UVSSA, was first cloned in UV(S)S-A cells, where nonsense and frameshift mutations corrected defective transcription-coupled repair (TCR) and stabilized ERCC6, restoring RNA polymerase II processing after UV damage ([PMID:22466612]).

Subsequent multi-patient studies identified three truncating UVSSA variants, including c.367A>T (p.Lys123Ter) and c.1040G>A (p.Trp347Ter), in UV(S)S-A individuals, demonstrating autosomal recessive inheritance with complete loss-of-function alleles and segregation in independent cohorts ([PMID:22466612]).

Whole exome sequencing in two consanguineous Pakistani pedigrees revealed a novel homozygous nonsense variant, c.1040G>A (p.Trp347Ter), in nine affected members, with full co-segregation, truncated protein mislocalization to the cytoplasm, and loss of nuclear UVSSA function ([PMID:31421932]).

A large multiplex Iranian kindred was later reported harboring the identical c.1040G>A (p.Trp347Ter) variant in UVSSA, co-segregating with UVSS in multiple relatives, expanding the mutational spectrum and supporting a founder effect in Middle Eastern populations ([PMID:38192884]).

All pathogenic UVSSA alleles reported to date are truncating (nonsense or frameshift), leading to loss of TC-NER function. The recurrent c.1040G>A (p.Trp347Ter) variant is observed across distinct ethnicities with allele frequency <0.001, consistent with autosomal recessive inheritance and high clinical penetrance.

Functional assays demonstrate that UVSSA interacts with USP7 via a TRAF-binding motif; truncated UVSSA fails to stabilize ERCC6, leading to persistent RNA polymerase II phosphorylation after UV irradiation. Ubiquitination studies of p.Lys414Arg further confirm the critical role of UVSSA in TC-NER and its proteasomal regulation ([PMID:29323787]).

Key Take-home: UVSSA truncating variants cause definitive autosomal recessive UV-sensitive syndrome through loss of transcription-coupled repair, supporting molecular diagnosis and potential gene-targeted interventions.

References

• Nature genetics | 2012 | Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair. PMID:22466612
• The FEBS journal | 2018 | Inhibition of UVSSA ubiquitination suppresses transcription-coupled nucleotide excision repair deficiency caused by dissociation from USP7. PMID:29323787
• 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
• Advanced biomedical research | 2023 | A Homozygous Nonsense Variant in UVSSA Causes UV-sensitive Syndrome from Very Large Kindred: The First Report from Iran. PMID:38192884

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