Xeroderma Pigmentosum Group G with Severe Neurological Involvement and Features of Cockayne Syndrome in Infancy

Zafeiriou, Dimitrios I.; Thorel, Fabrizio; Andreou, Alexander; Kleijer, Wim J.; Raams, Anja; Garritsen, Victor H.; Gombakis, N.; Jaspers, Nicolaas G. J.; Clarkson, Stuart G.

doi:10.1203/00006450-200103000-00016

Cited by 34 publications

(32 citation statements)

References 17 publications

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“…The other XPG allele produced a truncated protein of 175 amino acids. This patient died at 11 months (57). By contrast, two very mildly affected XP-G siblings who are now in their thirties, XP125LO and XP124LO, produce XPG of 959 amino acids from one allele and full-length XPG with an A792V substitution from the other (37,38).…”

Section: Resultsmentioning

confidence: 90%

“…Most CS patients have no XP connection and instead carry mutations in the CSA and CSB genes, but XP/CS symptoms are also found in XP-B and some XP-D individuals (26). The onset of CS in XP-G/CS patients is particularly early and severe, with reported life expectancies ranging from only months to less than 7 years (12,16,22,33,53,57).…”

mentioning

confidence: 99%

“…Mildly affected XP-G individuals can generate from one XPG allele the full-length protein of 1186 amino acids but with single missense mutations that inhibit its endonuclease function (8,12,37,38). A missense mutation has also been found in one allele of an XP-G baby with CS features (57), but this particular substitution (P72H) greatly destabilizes the protein (F. Thorel, unpublished data). All other examined XP-G/CS individuals produce truncated proteins from both XPG alleles (12, 38, 40; A. Pigni, unpublished data).…”

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confidence: 99%

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Definition of a Short Region of XPG Necessary for TFIIH Interaction and Stable Recruitment to Sites of UV Damage

Thorel¹,

Constantinou²,

Dunand-Sauthier³

et al. 2004

Molecular and Cellular Biology

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XPG is the human endonuclease that cuts 3 to DNA lesions during nucleotide excision repair. Missense mutations in XPG can lead to xeroderma pigmentosum (XP), whereas truncated or unstable XPG proteins cause Cockayne syndrome (CS), normally yielding life spans of <7 years. One XP-G individual who had advanced XP/CS symptoms at 28 years has been identified. The genetic, biochemical, and cellular defects in this remarkable case provide insight into the onset of XP and CS, and they reveal a previously unrecognized property of XPG. Both of this individual's XPG alleles produce a severely truncated protein, but an infrequent alternative splice generates an XPG protein lacking seven internal amino acids, which can account for his very slight cellular UV resistance. Deletion of XPG amino acids 225 to 231 does not abolish structure-specific endonuclease activity. Instead, this region is essential for interaction with TFIIH and for the stable recruitment of XPG to sites of local UV damage after the prior recruitment of TFIIH. These results define a new functional domain of XPG, and they demonstrate that recruitment of DNA repair proteins to sites of damage does not necessarily lead to productive repair reactions. This observation has potential implications that extend beyond nucleotide excision repair.

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Section: Resultsmentioning

confidence: 90%

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confidence: 99%

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confidence: 99%

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Definition of a Short Region of XPG Necessary for TFIIH Interaction and Stable Recruitment to Sites of UV Damage

Thorel¹,

Constantinou²,

Dunand-Sauthier³

et al. 2004

Molecular and Cellular Biology

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“…b-propeller is a circular arranged motif containing four-stranded [20]; Pro72His: a mutation found in an XP patient that impairs XPG endonuclease function [117]; Leu858Pro: a mutation found in an XP patient, that results in reduced endonuclease activity [118]; Ala874Thr: diminishes XPG activity to repair DNA damage in an XP patient [119]; Ala792Val: a mutation found in an XP patient XPG that eliminates XPG endonuclease activity and repair function [79] and results in undetectable 5 0 incision, most likely by disrupting the PPI with XPF-ERCC1 [79]; Asp812Ala: abolishes XPG endonuclease activity [79,120]; Leu65Pro: impairs DNA repair [121]; Asp77Ala/Glu and Glu791Ala/Asp: these mutations abolish XPG endonuclease activity [79,81]. The substitutions to Ala also abolish DNA repair and result in decreased XPG activity in the repair bubble, whereas substitutions to Glu and Asp, respectively, do not exhibit activity in the bubble substrate [79]; Arg992Ala and Arg992Glu: necessary for XPG binding to PCNA [87].…”

Section: ) a Wd40mentioning

confidence: 99%

Overview of xeroderma pigmentosum proteins architecture, mutations and post-translational modifications

Feltes

Bonatto

2015

Mutation Research/Reviews in Mutation Research

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“…The other allele encoded a full-length protein with a single amino acid substitution of the highly conserved proline 72 to histidine. 62 This allele does not confer any resistance to UV irradiation and the protein has been found to be highly unstable in overexpressed form, although the stability of this protein has not been assessed in cells of the patient directly. Based on these observation it is likely that the P72H mutation renders XPG completely unstable, resulting effectively in a null mutation.…”

Section: Patients With Severe Xp and Cs Symptomsmentioning

confidence: 99%

XPG: Its Products and Biological Roles

Schärer

Molecular Mechanisms of Xeroderma Pigmentosum

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Xeroderma pigmetosum patients of the complementation group G are rare. One group of XP-G patients displays a rather mild and typical XP phenotype. Mutations in these patients interfere with the function of XPG in the nucleotide excision repair, where it has a structural role in the assembly of the preincision complex and a catalytic role in making the incision 3' to the damaged site in DNA. Another set of XP-G patient is much more severely affected, displaying combined symptoms of xeroderma pigmentosum and Cockayne syndrome, referred to as XP/CS complex. Although the molecular basis leading to the XP/CS complex has not yet been fully established, current evidence suggests that these patients suffer from a mild defect in transcription in addition to a repair defect. Here, the history of how the XPG gene was discovered, the biochemical properties of the XPG protein, and the molecular defects found in XP-G patients and mouse models are reviewed.

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Xeroderma Pigmentosum Group G with Severe Neurological Involvement and Features of Cockayne Syndrome in Infancy

Cited by 34 publications

References 17 publications

Definition of a Short Region of XPG Necessary for TFIIH Interaction and Stable Recruitment to Sites of UV Damage

Definition of a Short Region of XPG Necessary for TFIIH Interaction and Stable Recruitment to Sites of UV Damage

Overview of xeroderma pigmentosum proteins architecture, mutations and post-translational modifications

XPG: Its Products and Biological Roles

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