DISEASE CARD

Disease group DNA repair disorders
DISEASE NAME UV-SENSITIVE SYNDROME
Synonymous -
Estimated prevalence currently comprises one French, one Israeli and five Japanese individuals
OMIM 600630
Inheritance Autosomal recessive
Gene (s) CSA/ERCC8 (609412), CSB/ERCC6 (609413), UVSSA/KIAA1530 (614632)

Definition

UV-sensitive syndrome (UVSS) is a rare autosomal recessive disorder first reported as a distinct clinical entity in 1994 (Itoh et al. Mutation Research 314:233-248, 1994). The patients affected by UVSS exhibit photosensitivity and mild skin abnormalities in sun exposed areas of the skin, with freckling and telangiectasia, with no skin cancers.

Cultured cells from UVSS patients are hypersensitive to ultraviolet (UV) light and, following UV irradiation, are unable to restore RNA synthesis rates to normal levels. This cellular phenotype is similar to that typically observed in Cockayne syndrome (CS) patients. UVSS is genetically heterogeneous, in that it is linked to mutations in the CSA/ERCC8, CSB/ERCC6 or UVSSA/KIAA1530 gene.

Clinical Description

The cardinal clinical features of UVSS are slight cutaneous photosensitivity and cutaneous pigmentation with freckles on the face and exposed areas, hypopigmented spots, telangiectasia, erythema, dried skin. The clinical phenotype closely resembles mild xeroderma pigmentosum. No neurological abnormalities, skin or internal cancers have been reported to date. Growth, mental development and life span are normal. However, it must be noted that the oldest known UVSS patient is about 50 years old.

Pathogenesis

Following exposure to ultraviolet (UV) light, cells from UVSS patients show reduced survival and recovery of DNA and RNA synthesis but normal capability to perform DNA repair synthesis. Genetic analysis led to the definition of three distinct complementation groups, CS-A and CS-B and UVSS-A. Like cells from CS patients, UVSS cells fail to perform preferential repair of the transcribed strand of transcriptionally active genes at the rate seen in normal cells, but they are capable of removing damage from the non-transcribed part of the genome at the normal rate. All activities whose alteration results in UVSS are involved in transcription-coupled repair, the nucleotide excision repair (NER) sub-pathway that specifically removes DNA damage blocking the progression of the transcription machinery in actively transcribed regions of DNA (TC-NER). Given the involvement of CSA and CSB not only in UVSS but also in CS, questions remain open for clinical pathology especially about the developmental and neurological impairment so evident in patients with CS but not in those with UVSS. The only consistent correlation between defects in TC-NER in all these individuals is with skin photosensitivity. As reported in the specific card, the CS proteins have additional functions including the repair of oxidative damage in DNA. Interestingly, cells of UVSS patients are UV-sensitive but they are not sensitive to oxidizing agents. 

Diagnosis

The diagnosis of UVSS is made clinically based on skin manifestations. Laboratory testing can be useful for confirming the suspected clinical diagnosis. The presence of repair defects in UVSS can be conclusively diagnosed by analyzing patient’s cells for the appropriate DNA repair defect. Specific functional assays on in vitro cultured fibroblasts from the patients (obtained from small skin biopsies) are available to evaluate the cellular response to UV light and to define the gene responsible for the DNA repair defect. Definition of the molecular defect by sequencing of the relevant gene allows genetic counselling of the families involved.

Treatment

The main goal of treatment is to protect oneself from UV exposure and thus prevent the damaging effects it can have on the skin. UVSS patients should follow the general precautionary measures reported for xeroderma pigmentosum patients