Uv-Sensitive Syndrome 3

A number sign (#) is used with this entry because UV-sensitive syndrome-3 (UVSS3) can be caused by homozygous mutation in the UVSSA gene (614632) on chromosome 4p16.

Description

UV-sensitive syndrome-3 is an autosomal recessive disorder characterized by cutaneous photosensitivity and slight dyspigmentation, without an increased risk of skin tumors. Patient cells show impaired recovery of RNA synthesis (RRS) after UV irradiation due to defective preferential repair of DNA damage in actively transcribing genes, although unscheduled DNA repair is normal. The cellular findings are consistent with a defect in transcription-coupled nucleotide excision repair (TC-NER) of UV damage (summary by Itoh et al., 1994 and Nakazawa et al., 2012).

For a general phenotypic description and a discussion of genetic heterogeneity of UVSS, see UVSS1 (600630).

Clinical Features

Fujiwara et al. (1985) reported a 16-year-old Japanese girl (XP24KO) with mild photosensitivity reminiscent of xeroderma pigmentosum (see, e.g., 278700). She had an acute sun sensitivity reaction without blistering at age 1 year. Small pigmented freckles and telangiectases were noted on her face at age 11-12 years. She had no neoplasia and no other abnormalities. Patient fibroblasts were twice as sensitive to UV killing as normal cells, and were reported to show a reduced level (30-55%) of unscheduled DNA synthesis (UDS) after irradiation. The patient was initially assigned to XP complementation group E (278740). However, reinvestigation of the XP24KO cells by Itoh et al. (2000) showed normal UDS and nucleotide excision repair, but decreased recovery of RNA synthesis after UV irradiation; the phenotype was reclassified as UVSS.

Kawada et al. (1986) reported a 5-year-old Japanese girl (XP70TO) with mild symptoms of xeroderma pigmentosum. She had neither skin malignancies nor neurologic abnormalities. Cellular studies showed UV sensitivity and reduced UV-induced unscheduled DNA synthesis, and the patient was initially assigned to XP complementation group E. However, cellular studies on XP70TO by Nakazawa et al. (2012) showed nearly normal UDS and markedly defective RRS, consistent with UVSS.

Itoh et al. (1994, 1996) reported 2 teenaged Japanese sibs with mild clinical manifestations similar to those of xeroderma pigmentosum: acute sunburn, dryness with freckling and pigmentation anomalies of sun-exposed skin, and telangiectasia without neurologic abnormalities or tumors. Each showed photosensitivity at about 6 months of age, with erythema and edema on sun-exposed skin a few hours after exposure. Patient cells showed impaired RRS after UV irradiation, although unscheduled DNA synthesis was normal. The patients did not belong to any complementation group of the xeroderma pigmentosum (XP; e.g., 278730) or Cockayne (CSB; 133540) syndromes. Itoh et al. (1995) found that postreplication repair in cells derived from these patients was normal, indicating that they could not be classified as XP variant. Neither transfection nor microinjection of the cells with the human DNA repair gene ERCC1 (126380), which is known not to correct any complementation groups of XP or CS, failed to correct the defect of these cells, indicating that they do not belong to the rodent complementation group 1. However, the defect in recovery of RNA synthesis after UV irradiation was restored by microinjection of HeLa cell extract. The cellular characteristics such as UV sensitivity and defective RRS after UV irradiation with normal unscheduled DNA synthesis were reminiscent of Cockayne syndrome. On the basis of these results, Itoh et al. (1995) proposed that these patients be included under a general category designated 'UV-sensitive syndrome.'

Inheritance

The transmission pattern of UVSS3 in the families reported by Itoh et al. (1994), Nakazawa et al. (2012), and Zhang et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

By exome sequencing of 2 cell lines (Kps3 and XP24KO) derived from 2 unrelated patients with UV-sensitive syndrome-3, Nakazawa et al. (2012) identified a homozygous truncating mutation in the UVSSA gene (K123X; 614632.0001). The patients had previously been reported by Itoh et al. (1994), and Fujiwara et al. (1985) and Itoh et al. (2000), respectively. Direct sequencing of the UVSSA gene identified 2 additional homozygous mutations in 2 unrelated patients (614632.0002 and 614632.0003, respectively); the latter patient had been reported by Kawada et al. (1986). All of the cell lines showed defective RNA synthesis recovery after UV irradiation, which was restored after expression of wildtype UVSSA. Unscheduled DNA synthesis was nearly normal. Pathogenic UVSSA mutations were not found in 61 individuals with Cockayne syndrome (see, e.g., CSA, 216400).

Zhang et al. (2012) used microcell-mediated chromosome transfers via mouse cells to identify the gene responsible for UVSS3 in the Kps3 cell line. The results indicated that the causative gene was on mouse chromosome 5. Sequencing of the UVSSA gene identified a homozygous K123X mutation in the Kps3 cell line and in the XP24KO cell line. Expression of wildtype UVSSA in Kps3 cells restored normal levels of recovery of RNA synthesis after UV irradiation and UV resistance. Zhang et al. (2012) noted that the Kps3 cell line is not hypersensitive to oxidative damage (Nardo et al., 2009), which may explain the mild phenotype.