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Other entities represented in this entry:
SNOMEDCT: 36454001; ORPHA: 1466, 191, 220295, 910; DO: 0110849;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q33.1 | Xeroderma pigmentosum, group G | 278780 | Autosomal recessive | 3 | ERCC5 | 133530 |
| 13q33.1 | Xeroderma pigmentosum, group G/Cockayne syndrome | 278780 | Autosomal recessive | 3 | ERCC5 | 133530 |
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).
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).
Cheesbrough (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.
Lalle et al. (2002) found that the first 2 patients reported with XPG (Cheesbrough, 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).
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. (Note that Figure 6 of the report of Nouspikel et al. (1997) was retracted under a Voluntary Exclusion Agreement between one of the authors, Steven A. Leaden, and the US Department of Health and Human Services. The other authors stated that the other findings and conclusions of the article were not challenged by retraction of Figure 6.)
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.
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.
Arlett, C. F., Harcourt, S. A., Lehman, A. R., Stevens, S., Ferguson-Smith, M. A., Morley, W. N. Studies on a new case of xeroderma pigmentosum (XP3BR) from complementation group G with cellular sensitivity to ionizing radiation. Carcinogenesis 1: 745-751, 1980. [PubMed: 11219864] [Full Text: https://doi.org/10.1093/carcin/1.9.745]
Cheesbrough, M. J. Xeroderma pigmentosum--a unique variant with neurologic involvement. Brit. J. Derm. 99 (Suppl. 16): 61 only, 1978. [PubMed: 698095]
Hoeijmakers, J. H. J. Human nucleotide excision repair syndromes: molecular clues to unexpected intricacies. Europ. J. Cancer 30A: 1912-1921, 1994. [PubMed: 7734202] [Full Text: https://doi.org/10.1016/0959-8049(94)00381-e]
Ichihashi, M., Fujiwara, Y., Uehara, Y., Matsumoto, A. A mild form of xeroderma pigmentosum assigned to complementation group G and its repair heterogeneity. J. Invest. Derm. 85: 284-287, 1985. [PubMed: 4031543] [Full Text: https://doi.org/10.1111/1523-1747.ep12276776]
Keijzer, W., Jaspers, N. G., Abrahams, P. J., Taylor, A. M., Arlett, C. F., Zelle, B., Takebe, H., Kinmont, P. D., Bootsma, D. A seventh complementation group in excision-deficient xeroderma pigmentosum. Mutat. Res. 62: 183-190, 1979. [PubMed: 492197] [Full Text: https://doi.org/10.1016/0027-5107(79)90231-8]
Lalle, P., Nouspikel, T., Constantinou, A., Thorel, F., Clarkson, S. G. The founding members of xeroderma pigmentosum group G produce XPG protein with severely impaired endonuclease activity. J. Invest. Derm. 118: 344-351, 2002. [PubMed: 11841555] [Full Text: https://doi.org/10.1046/j.0022-202x.2001.01673.x]
Norris, P. G., Hawk, J. L. M., Avery, J. A., Giannelli, F. Xeroderma pigmentosum complementation group G--report of two cases. Brit. J. Derm. 116: 861-866, 1987. [PubMed: 3620347] [Full Text: https://doi.org/10.1111/j.1365-2133.1987.tb04906.x]
Nouspikel, T., Lalle, P., Leadon, S. A., Cooper, P. K., Clarkson, S. G. A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G: implications for a second XPG function. Proc. Nat. Acad. Sci. 94: 3116-3121, 1997. Note: Retraction: Proc. Nat. Acad. Sci. 103: 19606 only, 2006. Figure 6 was retracted as part of a Voluntary Exclusion Agreement between the author Steven A. Leadon and the U.S. Department of Health and Human Services (HHS) through the Public Health Service and the Office of Research Integrity; see Notice of Findings of Scientific Misconduct from HHS (71 Federal Register 110 (June 8, 2006/Notices) pp 33308-33309). [PubMed: 9096355] [Full Text: https://doi.org/10.1073/pnas.94.7.3116]
Soltys, D. T., Rocha, C. R. R., Lerner, L. K., de Souza, T. A., Munford, V., Cabral, F., Nardo, T., Stefanini, M., Sarasin, A., Cabral-Neto, J. B., Menck, C. F. M. Novel XPG (ERCC5) mutations affect DNA repair and cell survival after ultraviolet but not oxidative stress. Hum. Mutat. 34: 481-489, 2013. [PubMed: 23255472] [Full Text: https://doi.org/10.1002/humu.22259]
Vermeulen, W., Jaeken, J., Jaspers, N. G. J., Bootsma, D., Hoeijmakers, J. H. J. Xeroderma pigmentosum complementation group G associated with Cockayne syndrome. Am. J. Hum. Genet. 53: 185-192, 1993. [PubMed: 8317483]
Zafeiriou, D. I., Thorel, F., Andreou, A., Kleijer, W. J., Raams, A., Garritsen, V. H., Gombakis, N., Jaspers, N. G. J., Clarkson, S. G. Xeroderma pigmentosum group G with severe neurological involvement and features of Cockayne syndrome in infancy. Pediat. Res. 49: 407-412, 2001. [PubMed: 11228268] [Full Text: https://doi.org/10.1203/00006450-200103000-00016]