Uv-Sensitive Syndrome 1

A number sign (#) is used with this entry because of evidence that UV-sensitive syndrome-1 (UVSS1) is caused by homozygous mutation in the ERCC6 gene (609413) on chromosome 10q11.

Cockayne syndrome type B (CSB; 133540) is an allelic disorder with a more severe phenotype, including neurologic and skeletal abnormalities.

Description

UV-sensitive syndrome-1 is an autosomal recessive disorder characterized by cutaneous photosensitivity and mild freckling, 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 Horibata et al., 2004).

Genetic Heterogeneity of UV-Sensitive Syndrome

See also UVSS2 (614621), caused by mutation in the ERCC8 gene (609412) on chromosome 5q12, and UVSS3 (614640), caused by mutation in the UVSSA gene (614632) on chromosome 4p16.

Clinical Features

Fujiwara et al. (1981) reported a Japanese boy, born of consanguineous parents, with UV sensitivity syndrome. The patient exhibited a number of freckles, hypopigmented spots, telangiectasia, and slightly dried skin in sun-exposed areas, but no growth retardation or neurologic abnormalities at age 8 years. Patient fibroblasts were 5-fold more sensitive to UV irradiation compared to control cells, although the response of obligatory heterozygotes was normal. Although unscheduled DNA synthesis (UDS) and other nucleotide-excision repair processes were normal, patient cells showed a defective recovery of DNA synthesis after UV irradiation. Fujiwara et al. (1981) concluded that the patient had a new photodermatosis with a specific defect in the recovery of post-UV DNA synthesis. Itoh et al. (1996) reported follow-up of the patient (UV81KO) reported by Fujiwara et al. (1981). The patient was noted as being photosensitive at age 3 months. He had no skin tumors, and growth and development were normal. Laboratory studies on patient fibroblasts showed a specific failure of RRS after UV irradiation, although UDS was normal. The biochemical findings were reminiscent of Cockayne syndrome, but the patient had no other abnormalities consistent with that disorder. Horibata et al. (2004) reported follow-up of the patient reported by Fujiwara et al. (1981), who was 33 years of age at the time of the report. He had been healthy except for abnormal photosensitivity. He was 183 cm tall and weighed 64 kg. He had a slightly dark basal skin color and numerous small spots of pigmentation on his face, the extensor surface of his forearms, and the back of his hands. He had had no skin cancers and no neurologic abnormalities.

Miyauchi-Hashimoto et al. (1998) reported a Japanese boy with atypical Cockayne syndrome whose only clinical manifestations were photosensitivity and pigmented freckles on sun-exposed areas. He showed photosensitivity at age 4 months and had severe recurrent sunburns. His skin showed pigmented freckling and scaling, particularly on the face. Cultured skin fibroblasts showed extreme UV sensitivity and a defect of recovery of RNA synthesis after UV radiation, but an almost normal amount of UDS. The clinical features and cellular characteristics of the patient were consistent with UVSS. However, the patient was assigned to Cockayne syndrome type B by complementation analysis. The report suggested that Cockayne syndrome has a wider spectrum than previously considered.

Molecular Genetics

To identify the gene responsible for UV-sensitive syndrome, Horibata et al. (2004) performed a microcell-mediated chromosome transfer based on the functional complementation of UV hypersensitivity. They found that a cell line from the patient described by Fujiwara et al. (1981) acquired UV resistance when human chromosome 10 was transferred. Because the gene responsible for Cockayne syndrome group B (ERCC6; 609413), which involves neurologic abnormalities and photosensitivity as well as a defect in transcription-coupled DNA repair of UV damage, is located on chromosome 10, Horibata et al. (2004) sequenced the ERCC6 gene and identified a homozygous null mutation (R77X; 609413.0009). This finding was surprising because a null mutation of the ERCC6 gene would be expected to result in the features of Cockayne syndrome, such as severe developmental and neurologic abnormalities. On the other hand, Horibata et al. (2004) found no mutation in the ERCC6 cDNA and normal amounts of ERCC6 protein in another cell line from an unrelated patient with UV-sensitive syndrome, indicating genetic heterogeneity of this condition. Hypotheses explaining the discrepancy between null mutation of the ERCC6 gene and absence of Cockayne syndrome features were presented.

In a Japanese patient with UVSS assigned to Cockayne syndrome type B based on complementation studies (Miyauchi-Hashimoto et al., 1998), Nakazawa et al. (2012) identified a homozygous R77X mutation in the ERCC6 gene.