UV-sensitive syndrome: Whole exome sequencing identified a nonsense mutation in the gene UVSSA in two consanguineous pedigrees from Pakistan.

BACKGROUND

UV-sensitive syndrome (UVS) is a rare autosomal recessive genodermatosis characterised by photosensitivity, and hyperpigmentation, freckling, and dryness of sun exposed areas. In contrast to other photosensitivity disorders, affected patients show no predisposition to cutaneous melanoma or neurological dysfunction. UVS results from a defect in the transcription-coupled nucleotide excision repair (TC-NER) mechanism. UVS can be caused by mutations in the genes ERCC8, ERCC6, and UVSSA.

OBJECTIVE

To determine the underlying genetic cause of UVS and its functional consequences in nine members of two large, unrelated consanguineous pedigrees from Pakistan.

METHODS

Genomic DNA from one affected member of each family was subjected to whole exome sequencing. The identified mutation was then validated via Sanger sequencing using samples from all available family members. Molecular cloning and mammalian cell cultures were used for the translation and localisation of wild type (WT) and mutant constructs.

RESULTS

A novel homozygous nonsense mutation, (c.1040G>A [p.(Trp347*)]), was detected in exon 6 of the UVSSA gene in both families. Sanger sequencing revealed co-segregation of the nonsense mutation with the UVS phenotype. Immunoblotting revealed the anticipated 81kDa band for the WT construct, and a truncated protein of around 39kDa for the mutant. In mutant samples, immunofluorescence revealed mislocalisation of UVSSA from the nucleus to the cytoplasm.

CONCLUSIONS

This is the first report of UVS in the Pakistani population and the fourth report of a disease-causing mutation in UVSSA. The study broadens the UVSSA mutational spectrum, and contributes to functional understanding of truncated UVSSA proteins.