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

Moslehi, Roxana; Kumar, Anil; Mills, James L.; Ambroggio, Xavier; Signore, Caroline; Dzutsev, Amiran

doi:10.1038/ejhg.2011.249

Cited by 13 publications

(21 citation statements)

References 56 publications

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“…The frequency of NICU admissions among XP neonates was smaller (Po0.0001) than for TTD neonates. 19 recently reported a literature review of the relationship of mutations in the DNA repair/transcription gene, XPD, with human prenatal development. They claim 'Gestational complications were first reported to be y associated with TTD based on our novel clinical observationsy' .…”

Section: Resultsmentioning

confidence: 99%

“…There are several reasons why we believe that the prediction by Moslehi et al 19 that mutations in the C-terminal region of XPD [8][9][10] cause pre-eclampsia may not be correct. There is a complex genotype-phenotype relationship between the location of mutations in the human XPD gene and the presence or absence of clinical features of XP or TTD.…”

Section: Moslehi Et Almentioning

confidence: 93%

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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: Resultsmentioning

confidence: 99%

Section: Moslehi Et Almentioning

confidence: 93%

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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“…Recent molecular epidemiological studies on pregnancy and neonatal abnormalities in the mothers of patients with XPD mutations showed that 94% of TTD pregnancies (16 of 17) have preterm delivery, pre-eclampsia, hemolysis, elevated liver enzymes and low platelets syndrome, prematurity, and low birth weight. In contrast, none of 17 XP pregnancies had these complications (35,36). It is worthwhile considering that the human placenta, whose function is to facilitate nutrient exchanges between the fetus and the mother, contains abundant ECM components and well-preserved endogenous growth factors.…”

Section: Discussionmentioning

confidence: 99%

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

Arseni

Lanzafame

Compe

et al. 2015

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

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Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in distinct clinical entities, including the cancerprone xeroderma pigmentosum (XP) and the multisystem disorder trichothiodystrophy (TTD), which share only cutaneous photosensitivity. Gene-expression profiles of primary dermal fibroblasts revealed overexpression of matrix metalloproteinase 1 (MMP-1), the gene encoding the metalloproteinase that degrades the interstitial collagens of the extracellular matrix (ECM), in TTD patients mutated in XPD compared with their healthy parents. The defect is observed in TTD and not in XP and is specific for fibroblasts, which are the main producers of dermal ECM. MMP-1 transcriptional up-regulation in TTD is caused by an erroneous signaling mediated by retinoic acid receptors on the MMP-1 promoter and leads to hypersecretion of active MMP-1 enzyme and degradation of collagen type I in the ECM of cell/tissue systems and TTD patient skin. In agreement with the well-known role of ECM in eliciting signaling events controlling cell behavior and tissue homeostasis, ECM alterations in TTD were shown to impact on the migration and wound-healing properties of patient dermal fibroblasts. The presence of a specific inhibitor of MMP activity was sufficient to restore normal cell migration, thus providing a potential approach for therapeutic strategies. This study highlights the relevance of ECM anomalies in TTD pathogenesis and in the phenotypic differences between TTD and XP.T he extracellular matrix (ECM) is a complex structural network that surrounds and supports cells within connective tissues. It generally includes three major types of macromolecules: fibrous proteins (collagens and elastic fibers), glycoproteins (such as fibronectins and laminins), and glycosaminoglycans/ proteoglycans. The type, amount and composition of the ECM give tissues their unique physical and biological properties (1). Notably, the ECM is not only a structural scaffold but also exhibits important functional roles in controlling key cellular events (e.g., adhesion, migration, proliferation, differentiation, and survival) involved in tissue homeostasis, development, inflammation, and tissue repair (2, 3). Thus, inherited or acquired structural alterations as well as metabolic disturbances of the ECM may cause cellular and tissue changes leading to the onset and progression of specific disorders, such as those affecting the connective tissues (osteogenesis imperfecta, Ehlers-Danlos syndrome, and Marfan's syndrome) or demanding ECM degradation (tumor invasion and metastasis) (4, 5). Recently, a reduced synthesis of the ECM component collagen type VI (COL6) was shown in confluent fibroblast cultures from patients with trichothiodystrophy [TTD; Online Mendelian Inheritance in Man (OMIM) #601675] (6), an autosomal recessive disorder characterized by symptoms affecting several tissues and organs (7). The most relevant features of TTD are hair abnormalities, ichthyotic skin, physical and mental retardation, neurodegeneration, and sign...

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“…It is possible that transcription is more demanding during mouse embryogenesis than in the human embryo, due to its more rapid development. In this respect it should be noted that TTD-causing mutations in the human XPD gene are associated with impaired placental development and other gestational complications [50].…”

Section: Discussionmentioning

confidence: 99%

Disruption of TTDA Results in Complete Nucleotide Excision Repair Deficiency and Embryonic Lethality

et al. 2013

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The ten-subunit transcription factor IIH (TFIIH) plays a crucial role in transcription and nucleotide excision repair (NER). Inactivating mutations in the smallest 8-kDa TFB5/TTDA subunit cause the neurodevelopmental progeroid repair syndrome trichothiodystrophy A (TTD-A). Previous studies have shown that TTDA is the only TFIIH subunit that appears not to be essential for NER, transcription, or viability. We studied the consequences of TTDA inactivation by generating a Ttda knock-out (Ttda−/−) mouse-model resembling TTD-A patients. Unexpectedly, Ttda−/− mice were embryonic lethal. However, in contrast to full disruption of all other TFIIH subunits, viability of Ttda−/− cells was not affected. Surprisingly, Ttda−/− cells were completely NER deficient, contrary to the incomplete NER deficiency of TTD-A patient-derived cells. We further showed that TTD-A patient mutations only partially inactivate TTDA function, explaining the relatively mild repair phenotype of TTD-A cells. Moreover, Ttda−/− cells were also highly sensitive to oxidizing agents. These findings reveal an essential role of TTDA for life, nucleotide excision repair, and oxidative DNA damage repair and identify Ttda−/− cells as a unique class of TFIIH mutants.

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

Cited by 13 publications

References 56 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

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

Disruption of TTDA Results in Complete Nucleotide Excision Repair Deficiency and Embryonic Lethality

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