Homozygous R788W Point Mutation in the XPF Gene of a Patient with Xeroderma Pigmentosum and Late-Onset Neurologic Disease

Sijbers, Anneke M.; Vader, Pieter; Snoek, J. W.; Raams, Anja; Jaspers, Nicolaas G. J.; Kleijer, Wim J.

doi:10.1046/j.1523-1747.1998.00171.x

Cited by 61 publications

(61 citation statements)

References 27 publications

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“…In fact, very few XP-F patients have developed skin cancers [see table 3 in Gregg et al (45), but note that contrary to what is indicated in this table, XP24BR and XP32BR have not had any skin cancers]. The few XP-F patients that have developed skin cancers did so as adults (47,48), mostly above the age of 40 y (46,(48)(49)(50). Nevertheless it appears that, whereas XP-C patients have pigmentary changes and skin cancers without abnormally severe sunburn reactions, XP-F patients, in direct contrast, have severe sunburn reactions with only modest pigmentary changes and relatively few skin cancers.…”

Section: Discussionmentioning

confidence: 89%

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

Fassihi

Sethi

Fawcett

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

171

202

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Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.UV radiation | nucleotide excision repair | skin cancer | ocular disease | neurodegeneration

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Section: Discussionmentioning

confidence: 89%

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

Fassihi

Sethi

Fawcett

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

171

202

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“…Neurologic involvement is also seen in some XP-B and XP-D patients [16]. Milder, adult onset neurologic impairment may be seen in XP-C and XP-F patients [17,18]. Neurologic disease has not been reported in XP-E(DDB2) patients [19].…”

Section: Neurological Disease In Xeroderma Pigmentosummentioning

confidence: 99%

Nucleotide excision repair deficient mouse models and neurological disease

Niedernhofer

2008

DNA Repair

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Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA base damage. A major substrate for NER is DNA damage caused by environmental genotoxins, most notably ultraviolet radiation. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three human diseases caused by inherited defects in NER. The symptoms and severity of these diseases vary dramatically, ranging from profound developmental delay to cancer predisposition and accelerated aging. All three syndromes include neurological disease, indicating an important role for NER in protecting against spontaneous DNA damage as well. To study the pathophysiology caused by DNA damage, numerous mouse models of NER deficiency were generated by knocking-out genes required for NER or knocking-in disease-causing human mutations. This review explores the utility of these mouse models to study neurological disease caused by NER deficiency.

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“…These patients carry a truncated version of the XPF protein caused by a frame shift mutation that inserts a premature stop codon in front of the ERCC1 binding domain or a point mutation, R788W, which is known to affect heterodimeric complex formation (41). Reduced concentrations of both the XPF and the ERCC1 proteins are observed in these patients, although the genes encoding XPF and ERCC1 are localized to different chromosomes (16).…”

mentioning

confidence: 99%

Biophysical Characterization of the Interaction Domains and Mapping of the Contact Residues in the XPF-ERCC1 Complex

Choi

Ryu

et al. 2005

Journal of Biological Chemistry

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XPF and ERCC1 exist as a heterodimer to be stable and active in cells and catalyze DNA cleavage on the 5-side of a lesion during nucleotide excision repair. To characterize the specific interaction between XPF and ERCC1, we expressed the human ERCC1 binding domain of XPF (XPF-EB) and the XPF binding domain of ERCC1 (ERCC1-FB) in Escherichia coli. Milligram quantities of a heterodimer were characterized with gel filtration chromatography, an Ni 2؉ -NTA binding assay, and analytical ultracentrifugation. Cross-linking experiments at high salt concentrations revealed that XPF interacts with ERCC1 mainly through hydrophobic interactions. XPF-EB was also shown to homodimerize in the absence of ERCC1. NMR cross-saturation methods were applied to map the residues involved in formation of the XPF-EB⅐XPF-EB homodimer and the XPF-EB⅐ERCC1-FB heterodimer. Helix H3 and the C-terminal region of XPF-EB were either within or in close proximity to the homodimer interface, whereas the ERCC1-FB binding site of XPF-EB was distributed across helix H1, a small part of H2, H3, and the C-terminal region, most of which exhibited large changes in chemical shift upon ERCC1 binding. The XPF-EB heterodimeric interface is larger than the XPF-EB homodimeric one, which could explain why XPF has a stronger affinity for ERCC1 than for a second molecule of XPF. The XPF binding sites of ERCC1 were located in helices H1 and H3 and in the C-terminal region, similar to the involved surface of XPF. We used cross-saturation data and the crystal structure of related proteins to model the two complexes.DNA lesions, which interfere with DNA replication, transcription, and recombination (1), occur as a result of exogenous and endogenous damaging agents, such as UV irradiation, products of oxidative stress, and DNA-reactive chemicals. To maintain the integrity of the genome, DNA lesions are efficiently removed by DNA repair pathways, such as the nucleotide excision repair pathway, which removes various types of bulky DNA adducts. During nucleotide excision repair, the 5Ј and 3Ј sides of a lesion are cut by two endonucleases, the XPF-ERCC1 heterodimeric complex and XPG, respectively (2-5). This dual incision is made asymmetrically around a lesion to allow its release as part of a larger DNA fragment (24 -32 nucleotides) (6 -8). The remaining gap is filled by DNA synthesis and ligation (9, 10).The XPF-ERCC1 complex cuts a variety of DNA substrates, including bubbles, stem-loops, splayed arms, and flaps (2,4,11,12). XPF contains the endonuclease activity, while ERCC1 likely modulates the specificity required for DNA incision (13). XPF and ERCC1 form a stable heterodimer in mammalian cells and in vitro, and various lines of evidence suggest that both ERCC1 and XPF are unstable in the absence of the respective partner of each (14 -18). The XPF-ERCC1 heterodimer is known to be formed through the interaction of their C-terminal domains, which each include two helix-hairpin-helix (HhH) 1 motifs (19 -21). However, a detailed characterization of the XPF-ERCC1 heterod...

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Homozygous R788W Point Mutation in the XPF Gene of a Patient with Xeroderma Pigmentosum and Late-Onset Neurologic Disease

Cited by 61 publications

References 27 publications

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

Nucleotide excision repair deficient mouse models and neurological disease

Biophysical Characterization of the Interaction Domains and Mapping of the Contact Residues in the XPF-ERCC1 Complex

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