Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD ( ERCC 2) repair/transcription gene

Abstract

The xeroderma pigmentosum group D (XPD) protein has a dual function, both in nucleotide excision repair of DNA damage and in basal transcription. Mutations in the XPD gene can result in three distinct clinical phenotypes, XP, trichothiodystrophy (TTD), and XP with Cockayne syndrome. To determine if the clinical phenotypes of XP and TTD can be attributed to the sites of the mutations, we have identified the mutations in a large group of TTD and XP-D patients. Most sites of mutations differed between XP and TTD, but there are three sites at which the same mutation is found in XP and TTD patients. Since the corresponding patients were all compound heterozygotes with different mutations in the two alleles, the alleles were tested separately in a yeast complementation assay. The mutations which are found in both XP and TTD patients behaved as null alleles, suggesting that the disease phenotype was determined by the other allele. If we eliminate the null mutations, the remaining mutagenic pattern is consistent with the site of the mutation determining the phenotype.

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

“…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. Many XP patients had the common p.R683W mutation combined with other mutations.…”

“…Some alleles have been considered as null, with no activity for some functions. 5 However, XPD has multiple functions and there is evidence that both XPD alleles contribute to the overall phenotype. 6 We previously reported on a patient with COFS/TTD (TTD373BE) having p.D681N and p.R616W mutations that were not in the C-terminal region but were near the common p.R683W XP-associated mutation.…”

“…Many XP patients had the common p.R683W mutation combined with other mutations. 2,5,6 In the TTD patients, the mutations involve the C-terminal region (p.A725T in TTD421BE, p.E731Rfs*14 in TTD355BE and p.R722W in TTD351BE) as well as other locations in the XPD protein. 2,22 The pregnancies yielding patients TTD421BE and TTD355BE had pre-eclampsia, but the pregnancy yielding patient TTD351BE did not have pre-eclampsia.…”

“…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. Mutations are spread out along the 761 amino-acid structure of XPD in both disorders 1,5,[8][9][10][11] The mutations may affect nucleotide-excision repair and/or transcription to different extents. 2,3 In addition, some mutations are found in both XP and TTD patients.…”

DNA adduct levels and DNA repair polymorphisms in traffic-exposed workers and a general population sample

“…#, reference category; OR, odds ratio; CI, confidence interval.-1 Below or above the median level of 11.2 DNA adducts per 10 9 nucleotides (after exclusion of 33 subjects with adducts levels below the detection limit of the method).-2 From unconditional logistic regression analysis including in the same model all the terms in the table plus age (years), smoking history (current, ex-and never smoker), XPD-751 genotype, body mass index (kg/m 2 ), total caloric intake and intakes of vitamin C and E. different domains of XPD may affect different protein interactions, resulting in the expression of different phenotypes. 36 We studied the same XPD-Lys751Gln polymorphism: this might have divergent effects in different DNA repair pathways, or other types of DNA damage, when compared to hydrophobic bulky DNA adducts we have measured. Another recent study, of relatively small size, found no effect of XPD, but some association between XRCC1 genotype and polyphenol DNA adducts.…”