Xeroderma Pigmentosum, Complementation Group G

A number sign (#) is used with this entry because of evidence that xeroderma pigmentosum complementation group G (XPG) and XPG/Cockayne syndrome are caused by homozygous or compound heterozygous mutation in the ERCC5 gene (133530) on chromosome 13q33.

Homozygous mutation in the ERCC5 gene can also cause cerebrooculofacioskeletal syndrome-3 (COFS3; 616570).

Description

For a general description of xeroderma pigmentosum, see XPA (278700), and of Cockayne syndrome, see CSA (216400). Complementation group G has one of the smallest series of cases (Arlett et al., 1980).

Clinical Features

Cheesbrough and Kinmont (1978) and Keijzer et al. (1979) reported the first individual with XP complementation group G. She was noted to have facial photosensitive erythema at age 3 months and blistering on exposed skin at 5 months. She was normal until age 11 years, when she showed unstable gait and began to show mental deterioration. She reached age 17 years with no keratoses or skin tumors. Physical examination showed microcephaly with mental retardation, intention tremor of the arms, ataxia, moderate spasticity, wide-based gait, and bilateral pes cavus. Cells derived from the patient exhibited a low level of excision repair (2%) and impaired post-replication repair characteristic of XP. Arlett et al. (1980) reported a second individual with XPG who was over 7 years old. These patients were reported before the relationship between xeroderma pigmentosum group G and Cockayne syndrome was appreciated (Lalle et al., 2002).

Norris et al. (1987) described a brother and sister, aged 14 and 12 years, respectively, with XP group G. Both patients manifested only mild cutaneous changes, with no UV-induced skin tumors, although abnormal sensitivity to UVB wavelengths was demonstrated by radiation monochromator skin testing. Physical and neurologic development was normal.

Vermeulen et al. (1993) reported genetic studies of 2 unrelated, severely affected patients with clinical characteristics of Cockayne syndrome but with a biochemical defect typical of xeroderma pigmentosum. By complementation analysis, using somatic cell fusion and nuclear microinjection of cloned repair genes, they assigned these 2 patients to XP complementation group G.

Zafeiriou et al. (2001) described a premature, small for gestational age infant girl with microphthalmia, bilateral congenital cataracts, hearing impairment, progressive somatic and neurodevelopmental arrest, and infantile spasms. She presented a massive photosensitive reaction with erythema and blistering after minimal sun exposure, which slowly gave rise to small skin cancers. Her skin fibroblasts were 10-fold more sensitive than normal to UV exposure due to a severe deficiency in nucleotide excision repair. By complementation analysis, the patient was assigned to the XPG group.

Molecular Genetics

Lalle et al. (2002) found that the first 2 patients reported with XPG (Cheesbrough and Kinmont, 1978; Keijzer et al., 1979; Arlett et al., 1980) produced XPG proteins with severely impaired endonuclease activity. Both patients were compound heterozygous for truncating mutations in the ERCC5 gene (133530.0009, 133530.0010) and another mutation (133530.0008 and 133530.0011, respectively). The mutant cells, unlike those from xeroderma pigmentosum group G/Cockayne syndrome patients, were capable of limited transcription-coupled repair of oxidative lesions. Lalle et al. (2002) suggested that the residual ERCC5 activity in these patients was responsible for the absence of severe early-onset Cockayne syndrome symptoms.

In a patient with XPG/CS, Zafeiriou et al. (2001) identified compound heterozygosity for 2 mutations in the ERCC5 gene (133530.0006; 133530.0007).

Genotype/Phenotype Correlations

Some patients with a combined phenotype of xeroderma pigmentosum and Cockayne syndrome fall into complementation group G. Nouspikel et al. (1997) demonstrated that patients with the combined phenotype XPG/CS have mutations that would produce severely truncated XPG proteins. In contrast, 2 sib XPG patients without CS were able to make full-length XPG, but had a missense mutation that inactivated its function in nucleotide excision repair (133530.0002). These results suggested that XPG/CS mutations abolish interactions required for a second important XPG protein function and that it is the loss of the second function that leads to the Cockayne syndrome clinical phenotype. Although Figure 6 of the report of Nouspikel et al. (1997) was retracted by Leadon, the remaining authors asserted that the validity of the conclusion was not challenged (Snyder, 2006).

Soltys et al. (2013) reported 2 Brazilian sibs, born of unrelated parents, with a mild form of XPG due to compound heterozygosity for 2 missense mutations in the ERCC5 gene (133530.0014 and 133530.0015). Both patients developed photosensitivity with mild skin lesions first apparent in infancy, but had no history of skin cancer or skin cancer precursor lesions up to ages 22 and 17 years, respectively. Patient cells showed a strong DNA repair defect in response to UV light, but not in response to oxidative stress. In vitro functional expression studies showed that both mutant proteins were able to partially restore activity in cells lacking ERCC5 in response to UV light, but not as well as the wildtype protein. In contrast, both mutant proteins showed activity comparable to wildtype in response to oxidative stress. Soltys et al. (2013) suggested that more severe ERCC5 defects that also impair the response to oxidative stress-induced injury, usually truncating mutations (see, e.g., 133530.0003), are associated with the more severe phenotype observed in Cockayne syndrome.

History

Complementation tests by cell fusion demonstrated that the NER syndromes are genetically heterogeneous and comprise 10 or more complementation groups: 7 in xeroderma pigmentosum, 2 in Cockayne syndrome, and 2 in TTD (Hoeijmakers, 1994). The finding of additional patients combining features of xeroderma pigmentosum and Cockayne syndrome within complementation groups XPB (610651), XPD (278730), and XPG indicated that there is considerable clinical heterogeneity with phenotypic overlap within the subsets of complementation groups.