Xeroderma pigmentosum (complementation group D) mutation is present in patients affected by trichothiodystrophy with photosensitivity

Stefanini, Miria; Lagomarsini, P.; Arlett, C.F.; Marinoni, S.; Borrone, C; Crovato, Franco; Trevisan, Giusto; Cordone, G; Nuzzo, Fiorella

doi:10.1007/bf00282072

Cited by 123 publications

(56 citation statements)

References 26 publications

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“…In addition, in attempting to evaluate the analysis by Moslehi and colleagues associating mutations in the C-terminal motif of XPD with TTD prenatal complications, we were unable to find mutation information in two of the three references cited. 15,21 Our XP and TTD patients had XPD mutations that are similar to those previously published. 1,5,[8][9][10][11] All of our XP and TTD patients were compound heterozygotes for two different XPD mutations.…”

Section: Discussionsupporting

confidence: 84%

Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum

et al. 2012

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The XPD(ERCC2) gene encodes a DNA helicase involved in DNA repair and transcription. Patients with mutations in XPD may have different autosomal recessive phenotypes including trichothiodystrophy (TTD) or xeroderma pigmentosum (XP). TTD patients have sulfur-deficient, brittle hair, short stature and developmental delay. In contrast, XP patients have freckle-like pigmentation and a greatly increased risk of sun-induced skin cancers. Mothers of TTD patients have been reported to have a high frequency of pregnancy and neonatal complications. We performed a molecular epidemiological study of 15 mothers of 17 TTD patients and 13 mothers of 17 XP patients, all with XPD mutations. We found that 94% (16/17) of the TTD pregnancies had pre-term delivery, pre-eclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, prematurity or low birth weight. None of the 17 XP pregnancies had these complications (Po0.001). As mutations in XPD may have differential effects on DNA repair and transcription, these observations should provide insights into the role of XPD in human pregnancy and fetal development. European Journal of Human Genetics (2012Genetics ( ) 20, 1308Genetics ( -1310 doi:10.1038/ejhg.2012; published online 23 May 2012Keywords: DNA repair; pre-eclampsia; transcription factor IIH INTRODUCTIONPatients with different mutations in the DNA repair/transcription helicase, XPD(ERCC2), may have markedly disparate autosomal recessive phenotypes, including trichothiodystrophy (TTD) or xeroderma pigmentosum (XP). 1-11 TTD patients have brittle hair, short stature, developmental delay and multisystem involvement without increased skin cancer risk. 12 In contrast, XP patients have sun sensitivity, freckle-like skin pigmentation, a 10 000-fold increase in skin cancer, and 25% have progressive neurologic degeneration. 12,13 At the National Institutes of Health (NIH), we have examined XP patients since 1971 and TTD patients since 2001 as part of a natural history protocol. 7,13 Our review of all English-language-published case reports of TTD patients found 112 TTD patients, of whom 55% had abnormal characteristics at birth and 28% had maternal pregnancy complications. 14 We then conducted two molecular epidemiological studies of pregnancy and neonatal abnormalities in mothers of TTD patients in our clinic. 15,16 We found that 81% of these pregnancies had complications, including 56% with preterm delivery, 30% with preeclampsia and 11% with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. 16 The TTD patients had mutations in TTD-A(GTF2H5) or TTDN1(C7orf11) in addition to XPD and unknown genes. In contrast, our 1987 review of all Englishlanguage-published case reports of XP patients did not identify a large number of pregnancy abnormalities in 830 XP case reports. 17 These patients had mutations in at least 8 different genes involved in nucleotide excision repair and polymerase function. 7 In order to determine the influence of the XPD gene, we now have conducted a molecular epidemiological s...

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Section: Discussionsupporting

confidence: 84%

Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum

et al. 2012

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“…8 Neonatal history was not reported for the one patient with XP/CS identified through the literature. 38 Mapping of preeclampsia-associated domains on XPD All TTD (n¼8) 8,20,21 and XP (n¼3) 30,36,37 cases with known XPD mutations and explicit information on presence or absence of preeclampsia were included in the analysis to map the preeclampsiaassociated alleles onto XPD. Of the eight TTD (including one COFS/TTD) pregnancies, four were associated with preeclampsia and all eight were associated with at least one prenatal complication.…”

Section: Resultsmentioning

confidence: 99%

“…21 In the fourth TTD case, the patient had an allele with severely compromised XPD gene (34-54fs, 55-760D) coupled to an allele with an insertion (E81V, S ins , K82E) in helix 3 of the second helicase domain. Similar to this latter TTD case, each of the three XP patients had an allele lacking the preeclampsia-associated motif (case 1: G47R:L461V, 716-730D; case 2: 189-760D:S541R; case 3: G675R:669-707fs, 708-760D).…”

Section: Resultsmentioning

confidence: 99%

Phenotype-specific adverse effects of XPD mutations on human prenatal development implicate impairment of TFIIH-mediated functions in placenta

et al. 2012

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Mutations in XPD (ERCC2), XPB (ERCC3), and TTD-A (GTF2H5), genes involved in nucleotide excision repair and transcription, can cause several disorders including trichothiodystrophy (TTD) and xeroderma pigmentosum (XP). In this study, we tested the hypothesis that mutations in the XPD gene affect placental development in a phenotype-specific manner. To test our hypothesis and decipher potential biologic mechanisms, we compared all XPD-associated TTD (n¼43) and XP (n¼37) cases reported in the literature with respect to frequencies of gestational complications. Our genetic epidemiologic investigations of TTD and XP revealed that the exact genetic abnormality was relevant to the mechanism leading to gestational complications such as preeclampsia. Through structural mapping, we localized the preeclampsia-associated mutations to a C-terminal motif and the helicase surfaces of XPD, most likely affecting XPD's binding to cdk-activating kinase (CAK) and p44 subunits of transcription factor (TF) IIH. Our results suggested a link between TTD-but not XP-associated XPD mutations, placental maldevelopment and risk of pregnancy complications, possibly due to impairment of TFIIH-mediated functions in placenta. Our findings highlight the importance of the fetal genotype in development of gestational complications, such as preeclampsia. Therefore, future studies of genetic associations of preeclampsia and other placental vascular complications may benefit from focusing on genetic variants within the fetal DNA.

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“…Miria Stefanini had shown that photosensitive TTD patients were defective in NER, like XP cells, and moreover were assigned to the XP-D complementation group [59]. We initiated a long-standing collaboration with Miria, extending her findings [60] and speculating and trying to understand how mutations in the XPD gene could result in such different phenotypes in XP and TTD.…”

Section: Xp Variants Cockayne Syndrome and Other Repair-deficient DImentioning

confidence: 99%

DNA repair, DNA replication and human disorders: A personal journey

Lehmann

2012

DNA Repair

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Xeroderma pigmentosum (complementation group D) mutation is present in patients affected by trichothiodystrophy with photosensitivity

Cited by 123 publications

References 26 publications

Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum

Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum

Phenotype-specific adverse effects of XPD mutations on human prenatal development implicate impairment of TFIIH-mediated functions in placenta

DNA repair, DNA replication and human disorders: A personal journey

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