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

Abstract

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...

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

“…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.…”

ERCC2 mutations in two siblings with a severe trichothiodystrophy phenotype

“…ERCC2 is a component of transcription factor IIH (TFIIH), essential for basal transcription and nucleotide excision repair, which is disturbed in TTD patients. Other subunits of TFIIH are ERCC3 (mutations lead to photosensitive TTD2 and to XP group B) and GTF2H5 (mutations lead to photosensitive TTD3), but ERCC2 (XPD) is most frequently mutated . Alternations in the ERCC2 subunit may lead to multiple phenotypes other than TTD: xeroderma pigmentosum (XP), Cockayne syndrome (CS), cerebro‐oculo‐facio‐skeletal (COFS) syndrome and a complex overlap phenotype .…”

“…Newborns frequently present with a collodion membrane, followed by ichthyosis of the skin and nail deformities like brittleness, koilonychia and onychoschizia. Additional important features of TTD include pregnancy and birth complications, growth restriction, neurological impairment, gonadal dysgenesis, haematological and ophthalmological abnormalities and recurrent life‐threatening infections . Moreover, TTD is associated with an up to 20‐fold increased risk of death before the age of 10 years.…”

“…Additional important features of TTD include pregnancy and birth complications, growth restriction, neurological impairment, gonadal dysgenesis, haematological and ophthalmological abnormalities and recurrent life-threatening infections. [7][8][9][10] Moreover, TTD is associated with an up to 20-fold increased risk of death before the age of 10 years. The broad spectrum of anomalies is caused by mutations in the DNA transcription-repair genes XPD (ERCC2), XPB (ERCC3) and TTDA (GTF2H5), all subunits of the transcription/repair factor TFIIH, or by mutations in TTDN1 (C7ORF11), a gene with unknown function.…”

Reproductive outcomes in pregnant women aged 35 or older: the role of individual repair capacity

“…TTD-1 is characterised by brittle sulphur-deficient hair, photosensitivity, developmental abnormalities and reduced life span [109]. Pregnancies with a TTDaffected foetus were retrospectively shown to have had abnormally high rates of pregnancy complications (placentation abnormalities, HELLP syndrome, preeclampsia), abnormal levels of routine biochemical markers, a significant percentage (70 %) of low birth weight infants (half of which were below the 10th percentile for gestational age) and were significantly more likely to have been delivered prematurely by emergency caesarean section because of fetal distress [110]. TTD-1 is caused by mutations in the gene XPD (ERCC2), coding for a DNA helicase unwinding the DNA at the site of damage and allowing unimpeded access of the cellular machinery for nucleotide excision repair (NER) [109].…”