* 126340

ERCC EXCISION REPAIR 2, TFIIH CORE COMPLEX HELICASE SUBUNIT; ERCC2


Alternative titles; symbols

EXCISION REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 2; DNA REPAIR DEFECT EM9 OF CHINESE HAMSTER OVARY CELLS, COMPLEMENTATION OF; EM9
XPD GENE; XPD


HGNC Approved Gene Symbol: ERCC2

Cytogenetic location: 19q13.32     Genomic coordinates (GRCh38): 19:45,349,837-45,370,573 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
19q13.32 ?Cerebrooculofacioskeletal syndrome 2 610756 AR 3
Trichothiodystrophy 1, photosensitive 601675 AR 3
Xeroderma pigmentosum, group D 278730 AR 3

TEXT

Description

ERCC2 is a subunit of the TFIIH transcription/repair factor, which functions as a DNA helicase for nucleotide excision repair (Coin et al., 1998).


Cloning and Expression

Weber et al. (1988) used the UV-sensitive Chinese hamster ovary (CHO) cell line UV5, which is defective in the incision step of nucleotide excision repair (NER), to identify and clone a complementing human gene, ERCC2.

Using a human fibroblast expression cDNA library to complement radiosensitivity in UV5 cells, followed by examining genomic DNA, Weber et al. (1990) identified full-length ERCC2. The deduced 760-amino acid protein has a calculated molecular mass of 86.9 kD. Comparison with yeast rad3 revealed a putative ATP-binding box, a DNA-binding box, and other domains common to the helicase superfamily. Within the conserved domains, ERCC2 and rad3 are 73.8% identical and 88.5% homologous. ERCC2 also has a highly basic 14-amino acid putative nuclear localization signal.


Gene Function

Flejter et al. (1992) demonstrated that the ERCC2 gene corrected the sensitivity to ultraviolet (UV) radiation and defective nucleotide excision repair in xeroderma pigmentosum cells of complementation group D (XPD; 278730). The XPD cell line used in these studies was GM08207. They first demonstrated correction by the transfer of a rearranged human chromosome by the method of microcell-mediated chromosome transfer (MMCT). Then, having demonstrated that the rearranged chromosome involved human chromosomes 16 and 19, including the region of the latter chromosome containing the ERCC2 gene, they directly transferred a cosmid containing the ERCC2 gene into XPD cells and showed that UV resistance was conferred thereby. Flejter et al. (1992) further identified a single rearranged human chromosome, designated Tneo, that corrected the UV sensitivity and excision repair defect of XPD cells in culture. They went on to analyze the complex rearrangement involving material from chromosomes 16, 17, and 19 and showed that the 19q13.2-q13.3 region was included.

The ERCC2 gene is homologous to the RAD3 gene of the budding yeast Saccharomyces cerevisiae and the Rad15+ of the fission yeast Schizosaccharomyces pombe (Friedberg, 1992). Sung et al. (1993) purified the XPD protein to near homogeneity and showed that it possesses single-stranded DNA-dependent ATPase and DNA helicase activities. Expression of the human XPD gene in S. cerevisiae complemented the lethal defect of a mutation in the RAD3 gene.

In most cases, patients with XPD and trichothiodystrophy (TTD; see 601675) carry mutations in the carboxy-terminal domain of the XPD helicase, which is one of the subunits of the transcription/repair factor TFIIH. Coin et al. (1998) demonstrated that XPD (ERCC2) interacts specifically with p44 (GTF2H2; 601748), another subunit of TFIIH, and that this interaction results in the stimulation of 5-prime-to-3-prime helicase activity. Mutations in the XPD C-terminal domain, as found in most patients, prevent the interaction with p44, thus explaining the decrease in XPD helicase activity and the NER defect.

Inherited mutations of the TFIIH helicase subunits XPB (ERCC3; 133510) or XPD yield overlapping DNA repair and transcription syndromes. The high risk of cancer in these patients is not fully explained by the repair defect. The transcription defect, however, is subtle and more difficult to evaluate. Liu et al. (2001) showed that XPB and XPD mutations block transcription activation by the FUSE-binding protein (FBP; 603444), a regulator of MYC (190080) expression, and block repression by the FBP-interacting repressor (FIR; 604819). Through TFIIH, FBP facilitates transcription until promoter escape, whereas after initiation, FIR uses TFIIH to delay promoter escape. Mutations in TFIIH that impair regulation by FBP and FIR affect proper regulation of MYC expression and have implications in the development of malignancy.

In cells derived from XPD patients, Keriel et al. (2002) observed a reduction of the ligand-dependent transactivation mediated by several nuclear receptors: retinoic acid receptor-alpha (RARA; 180240), estrogen receptor-alpha (133430), and androgen receptor (313700). They demonstrated that the XPD mutation alters cyclin-dependent kinase-7 (CDK7; 601955) function in RARA phosphorylation. Transactivation was restored upon overexpression of either wildtype XPD or RARA containing a ser77-to-glu (S77E) mutation, which mimics phosphorylated RARA. Thus, the authors demonstrated that the CDK7 kinase of TFIIH phosphorylates the nuclear receptor, allowing ligand-dependent control of the activation of the hormone-responsive genes.

The CDK-activating kinase, or CAK complex, consists of CDK7 cyclin H (CCNH; 601953) and MAT1 (MNAT1; 602659). As the kinase subunit of TFIIH, CDK7 participates in basal transcription by phosphorylating the carboxy-terminal domain of the largest subunit of RNA polymerase II. As part of CAK, CDK7 also phosphorylates other CDKs, an essential step for their activation. Chen et al. (2003) showed that the Drosophila TFIIH component Xpd, whose human homolog is ERCC2, negatively regulates the cell cycle function of Cdk7, the CAK activity. Excess Xpd titrated CAK activity, resulting in decreased Cdk T-loop phosphorylation, mitotic defects, and lethality, whereas a decrease in Xpd resulted in increased CAK activity and cell proliferation. Moreover, Chen et al. (2003) showed that Xpd is downregulated at the beginning of mitosis when Cdk1 (116940), a cell cycle target of Cdk7, is most active. Downregulation of Xpd thus seems to contribute to the upregulation of mitotic CAK activity and to regulate mitotic progression positively. Chen et al. (2003) concluded that the downregulation of Xpd might be a major mechanism of mitotic silencing of basal transcription.

Yoder et al. (2006) showed that transduction by human immunodeficiency virus (HIV) or Moloney murine leukemia virus was substantially greater in XPB or XPD mutant cells than in isogenic complemented cells or XPA (611153) mutant cells. The difference in transduction efficiency was not due to apoptosis. Yoder et al. (2006) concluded that XPB and XPD reduce retroviral integration efficiency by enhancing degradation of retroviral cDNA, thereby reducing the available pool of cDNA molecules for integration.

Rudolf et al. (2006) identified a conserved domain that includes an iron-sulfur (Fe-S) cluster near the N termini of XPD and FANCJ (BRIP1; 605882). Three absolutely conserved cysteines provide ligands for the Fe-S cluster, and Rudolf et al. (2006) showed that the cluster is essential for XPD helicase activity. Yeast strains harboring mutations in the Fe-S domain of Rad3 retained their overall fold and stability and could hydrolyze ATP in a single-stranded DNA-dependent manner, but they were defective in nucleotide excision repair of UV-induced damage.

Orioli et al. (2013) found that skin of TTD patients with mutations in the ERCC2 gene had reduced content of COL6A1 (120220), an abundant collagen of skin and connective tissue. In culture, dermal fibroblasts from TTD patients failed to induce COL6A1 upon achieving confluence. XPD skin and cultured XPD fibroblasts with mutations in the ERCC2 gene did not show the same defects. Transfection of wildtype ERCC2 into TTD patient fibroblasts permitted induction of COL6A1 upon confluence. In silico analysis identified a putative SREBP1 (184756)-binding site in the COL6A1 promoter, and deletion of this site resulted in increased transcriptional activity from the COL6A1 promoter. Overexpression of wildtype ERCC2 in TTD patient fibroblasts resulted in RNA polymerase II and SP1 (189906) occupancy at the COL6A1 promoter, concomitant with loss of SREBP1 binding. Removal of SREBP1 from the COL6A1 promoter was also dependent on ATP hydrolysis. Orioli et al. (2013) concluded that ERCC2 in the TFIIH helicase removes SREBP1 from the COL6A1 promoter in an ATP-dependent manner and that, in TTD fibroblasts, mutated ERCC2 fails to displace the SREBP1 repressor from the COL6A1 promoter, resulting in inability to effect COL6A1 transcriptional upregulation in response to cell confluence.


Gene Structure

Frederick et al. (1994) characterized the genomic structure of the XPD (ERCC2) gene and found that it contains 23 exons ranging in size from 5 bp (exon 1) to 169 bp (exon 11).

Weber et al. (1990) determined that the 5-prime flanking region of the ERCC2 gene contains a classical TATA box, a reverse CAAT box, and a GC box. It also has a 34-base pyrimidine-rich region and a 12-base inverted repeat with 2 central bases of noncomplementarity.


Mapping

By somatic cell hybridization, Siciliano et al. (1985) assigned to human chromosome 19 a gene that complements a DNA repair defect in Chinese hamster ovary (CHO) cells called EM9. A second DNA repair defect of CHO cells, UV20 (ERCC1; 126380), was likewise corrected by human chromosome 19, which appears to be homologous to hamster chromosome 9; both contain GPI (172400) and PEPD (613230). In CHO cells, chromosome 9 is hemizygous. Thus, the findings probably indicate that 2 DNA repair genes are part of the homologous synteny group in these 2 species. By large fragment restriction enzyme site mapping, Mohrenweiser et al. (1989) found that ERCC1 and ERCC2 are separated by less than 250 kb. Greatly increased sister chromatid exchanges are characteristic of EM9 cells (Thompson et al., 1982), as in Bloom syndrome (210900).


Molecular Genetics

In cell lines from patients with xeroderma pigmentosum group D (XPD; 278730), Frederick et al. (1994) identified mutations in the ERCC2 gene (126340.0001-126340.0002).

Botta et al. (1998) determined the mutations and the pattern of inheritance of the XPD alleles in 11 patients with trichothiodystrophy identified in Italy. In all of the patients, the hair abnormalities diagnostic for TTD were associated with different disease severity but similar cellular photosensitivity. They identified 8 causative mutations, 4 of which had not previously been described, either in TTD or XP cases, supporting their hypothesis that the mutations responsible for TTD are different from those found in other pathologic phenotypes. The arg112-to-his (R112H; 126340.0006) mutation was the most common one found in the Italian patients, 5 of whom were homozygous and 2 heterozygous, for this mutation. Patients with this mutation had been reported by Battistella and Peserico (1996), Marinoni et al. (1991), Stefanini et al. (1992), Peserico et al. (1992), and Stefanini et al. (1993). Microscopic study of the hair showed pili torti, trichoschisis, and trichorrhexis nodosa. Polarization microscopy revealed a typical appearance of alternating light and dark bands, giving a 'tiger tail' pattern. Photosensitivity was reported in all patients, in association with the other symptoms typical of TTD, namely, ichthyosis, delayed physical and mental development, nail dysplasia, a face characterized by receding chin, small nose, and large ears, and microcephaly. Seven patients were still alive at ages 4 to 30 years; the 4 patients who died during early infancy showed severe physical and mental retardation and suffered from frequent respiratory infections. The 3 oldest patients, all women, aged 30, 20, and 21 years, had moderate mental and physical handicaps. They developed freckles during childhood, but progression to malignancy had not been observed. They had short stature (140 cm), began to menstruate at age 18 years, and were no longer prone to infections, although they suffered moderate infections during early childhood.

Kleijer et al. (1994) described a trichothiodystrophy patient (TTD1RO) with unusual additional features: during repeated episodes of pneumonia, she lost all her 'brittle' hair in 1 or 2 days, though it did regrow to the usual length after recovery. Concomitantly, her skin symptoms showed a transient, reversible deterioration. The patient was found by Takayama et al. (1996) to carry 2 unique point mutations in XPD: an arg658-to-cys (R658C; 126340.0007) amino acid substitution on one allele and a gly713-to-arg (G713R; 126340.0008) change on the other. In a screening of various TTD cases, Vermeulen et al. (2001) detected the R658C mutation in a female patient (TTD1DOD) of different ethnic background who was previously reported by Hansen et al. (1993). In conditions of high fever, she also exhibited unusual sudden hair loss, and her signs of ataxia were transiently aggravated. An affected brother and a patient from a related family showed the same manifestations. Thus, the R658C change was the phenotype-determining allele. Vermeulen et al. (2001) found that cells from these patients show an in vivo temperature-sensitive defect of transcription and DNA repair due to thermoinstability of TFIIH. Vermeulen et al. (2001) noted that temperature-sensitive mutations with manifestations associated with fever have been described rarely: see, e.g., hemoglobin Zurich (141900.0310) and antithrombin-III Rouen VI (107300.0046).

Broughton et al. (2001) identified 2 patients with some features of both XP and TTD. A 3-year-old girl with sun sensitivity and mental and physical developmental delay was compound heterozygous for mutations in the ERCC2 gene (126340.0011-126340.0012). Cultured cells from this patient demonstrated barely detectable levels of nucleotide excision repair. The other patient, a 28-year-old woman with sun sensitivity, pigmentation changes, and skin cancers typical of XP, had an arg112-to-his mutation (R112H; 126340.0006), seen previously in TTD patients, on one allele and a leu485-to-pro mutation (L485P; 126340.0013) on the other allele. The level of UV damage repair in the second patient was substantially higher than that in other patients with the same mutation. In both patients, polarized light microscopy revealed a tiger-tail appearance of the hair, and amino acid analysis of the hairshafts showed levels of sulfur-containing proteins between those of normal and TTD individuals.

Graham et al. (2001) reported involvement of the ERCC2 gene in a case of UV-sensitive COFS syndrome (214150), with compound heterozygosity for an arg616-to-trp null mutation (R616W; 126340.0010), previously found in a patient with XPD by Taylor et al. (1997), and a novel asp681-to-asn mutation (D681N; 126340.0009). They demonstrated, in a triplet pregnancy and in a subsequent singleton pregnancy, how the findings of abnormal DNA repair could be used for prenatal diagnosis of COFS syndrome.

In 5 XPD cell strains tested, Kobayashi et al. (2002) identified 6 positive disease-causing mutations in the ERCC2 gene. Each cell line was a compound heterozygote with different mutations. In each, 1 allele was thought to be functionally null and the other was a less severe allele with 3 mutations. The second allele in each strain was specific to the XP phenotype. Kobayashi et al. (2002) interpreted the results as consistent with the hypothesis that the site of mutation in the ERCC2 gene determines the clinical phenotype, XP or TTD.

Viprakasit et al. (2001) showed that the specific mutations in the ERCC2 gene that cause TTD result in reduced expression of the beta-globin (HBB; 141900) genes in these individuals. Eleven TTD patients with characterized mutations in the XPD gene were found to have the hematologic features of beta-thalassemia trait, and reduced levels of beta-globin synthesis and beta-globin mRNA. All of these parameters were normal in 3 patients with XP. The authors hypothesized that many of the clinical features of TTD may result from inadequate expression of a diverse set of highly expressed genes.

Reviews

Cleaver et al. (1999) tabulated the very large number of mutations that had been identified in the XPD gene in patients with diverse phenotypes.


Genotype/Phenotype Correlations

Taylor et al. (1997) identified the mutations in a large group of TTD and XPD patients to determine if the clinical phenotypes of XP and TTD could be attributed to the sites of the mutations. Most sites of mutations differed between XP and TTD, but there were 3 sites at which the same mutation was found in XP and TTD patients. Since the corresponding patients were all compound heterozygotes with different mutations in the 2 alleles, the alleles were tested separately in a yeast complementation assay. The mutations that were found in both XP and TTD patients behaved as null alleles, suggesting that the disease phenotype was determined by the other allele. When Taylor et al. (1997) eliminated the null mutations, the remaining mutagenic pattern was consistent with the site of the mutation determining the phenotype. Changes at arg683 were clearly associated with XP, whereas arg112his, arg722trp, and changes at arg658 appeared to be associated with TTD. They cited unpublished observations of a TTD patient of Turkish origin who was homozygous for the arg658cys change previously found in 1 allele of a TTD patient, suggesting that this allele is sufficient for the TTD phenotype. The 6 mutational changes of arginine residues observed at these 4 sites were all C-to-T or G-to-A mutations at CpG sites, which are presumed to result from deamination of 5-methylcytosine to thymine.

Petrini (2000) and Lehmann (2001) noted that the diversity of clinical outcomes associated with XPD and XPB mutations appeared to be explained by allele-specific mutations.


Animal Model

De Boer et al. (1998) generated a mouse model for trichothiodystrophy by gene-cDNA fusion targeting and introduction of the ERCC2/XPD arg722-to-trp (R722W; 126340.0014) mutation in the mouse, thereby mimicking the causative XPD point mutation of a TTD patient. TTD R722W/R722W mice reflect to a remarkable extent the human disorder, including brittle hair, developmental abnormalities, reduced life span, UV sensitivity, and skin abnormalities. The cutaneous symptoms are associated with reduced transcription of a skin-specific gene, SPRR2 (182267), strongly supporting the concept of TTD as a human disease due to inborn defects in basal transcription and DNA repair.

De Boer et al. (2002) found that mice with the R722W mutation in ERCC2 had many symptoms of premature aging, including osteoporosis and kyphosis, osteosclerosis, early graying, cachexia, infertility, and reduced life span. TTD mice carrying an additional mutation in XPA, which enhances the DNA repair defect, showed a greatly accelerated aging phenotype, which correlated with an increased cellular sensitivity to oxidative DNA damage. De Boer et al. (2002) hypothesized that aging in TTD mice is caused by unrepaired DNA damage that compromises transcription, leading to functional inactivation of critical genes and enhanced apoptosis.


ALLELIC VARIANTS ( 15 Selected Examples):

.0001 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE, INCLUDED
ERCC2, LEU461VAL
  
RCV000018267...

Xeroderma Pigmentosum, Complementation Group D

In cell line GM436 from a patient with xeroderma pigmentosum complementation group D (XPD; 278730), Frederick et al. (1994) identified a 1411C-G transversion in the ERCC2 gene, predicted to result in a leu461-to-val (L461V) substitution.

Trichothiodystrophy 1, Photosensitive

Takayama et al. (1997) studied a male patient with typical features of trichothiodystrophy (TTD1; 601675), including brittle hair, ichthyosis, characteristic face with receding chin and protruding ears, sun sensitivity, and mental and growth retardation. The relative amount of nucleotide excision repair (NER) carried out by a fibroblast cell strain from the patient after ultraviolet exposure was approximately 65% of normal as determined by a method that converted repair patches into quantifiable DNA breaks. UV survival curves showed a reduction in survival only at doses greater than 4 joules per square meter. Sequence analysis of the ERCC2 gene showed a leu461-to-val (L461V; 126340.0001) substitution and a deletion of amino acids 716-730 on one allele and an ala725-to-pro (A725P; 126340.0003) substitution on the other allele. The L461V mutation had been reported in a patient with xeroderma pigmentosum group D by Frederick et al. (1994) and in 2 other trichothiodystrophy patients (see Takayama et al., 1996), whereas the A725P mutation had not previously been reported. Comparisons suggested that the A725P mutation correlated with TTD with intermediate UV sensitivity.


.0002 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, GLN726TER
  
RCV000018269

In cell line XP67MA from a patient with xeroderma pigmentosum complementation group D (XPD; 278730), Frederick et al. (1994) identified a 2176C-T transition in exon 22 of the ERCC2 gene, changing codon 726 from CAG (gln) to TAG (stop). The mutation was predicted to produce a protein truncated by 34 amino acids. Although expression of the normal XPD cDNA could be shown to correct the UV sensitivity phenotype in XPD cells, cDNA constructs bearing either this or the L461V mutation (126340.0001) failed to yield complementation.


.0003 TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE

ERCC2, ALA725PRO
  
RCV000018270...

For discussion of the ala725-to-pro (A725P) mutation in the ERCC2 gene that was found in compound heterozygous state in a patient with photosensitive trichothiodystrophy (TTD1; 601675) by Takayama et al. (1997), see 126340.0001.


.0004 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, 4-BP DEL, NT668
  
RCV002266015...

Kobayashi et al. (1997) reported 2 causative mutations of the XPD gene in a Japanese patient with xeroderma pigmentosum complementation group D (XPD; 278730) and only mild skin symptoms of the disorder, without Cockayne syndrome, trichothiodystrophy, or other neurologic complications. One of the mutations in this compound heterozygote was a 4-bp deletion at nucleotides 668 to 671, resulting in frameshift and premature termination. The other was a nucleotide substitution leading to conversion of serine-541 to arginine (S541R; 126340.0005) in helicase domain IV of the XPD protein. The patient's father was heterozygous for the deletion, whereas the mother was heterozygous for the S541R mutation. An expression study showed that the XPD cDNA containing the deletion or the S541R missense mutation failed to restore UV sensitivity of XPD cells, whereas the wildtype XPD cDNA restored it to the normal level.


.0005 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, SER541ARG
  
RCV000018272

For discussion of the ser541-to-arg (S541R) mutation in the XPD gene that was found in compound heterozygous state in a patient with xeroderma pigmentosum complementation group D (XPD; 278730) by Kobayashi et al. (1997), see 126340.0004.


.0006 TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE

XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D, INCLUDED
ERCC2, ARG112HIS
  
RCV000018273...

Trichothiodystrophy 1, Photosensitive

Of 11 reported Italian patients with photosensitive trichothiodystrophy-1 (TTD1; 601675), Botta et al. (1998) noted that 5 were homozygous for an arg112-to-his (R112H) mutation in the ERCC2 gene and 2 were compound heterozygous.

Xeroderma Pigmentosum, Complementation Group D

Broughton et al. (2001) described a 28-year-old woman with sun sensitivity, pigmentation changes, and skin cancers typical of xeroderma pigmentosum complementation group D (XPD; 278730). Mutation analysis revealed compound heterozygous mutations in the ERCC2 gene: the R112H mutation and a leu485-to-pro (L485P; 126340.0003) substitution.


.0007 TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE

ERCC2, ARG658CYS
  
RCV000018275...

In a girl with photosensitive trichothiodystrophy-1 (TTD1; 601675), Takayama et al. (1996) found a C-to-T transition at nucleotide position 2050 of the ERCC2 gene, resulting in an arg658-to-cys amino acid change (R658C). The causative mutation on the other allele was identified as gly713-to-arg (G713R; 126340.0008). Ichthyosis and loss of scalp hair occurred intermittently in the patient.

In 2 patients with trichothiodystrophy with the unusual additional feature of aggravation during fever, Vermeulen et al. (2001) found an R658C mutation in the ERCC2 gene.


.0008 TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE

ERCC2, GLY713ARG
  
RCV000018276...

In a girl with photosensitive trichothiodystrophy-1 (TTD1; 601675), Takayama et al. (1996) found a G-to-C transversion at nucleotide position 2215 of the ERCC2 gene, resulting in a gly713-to-arg amino acid substitution. They identified this mutation in compound heterozygous state with R658C (126340.0007).


.0009 CEREBROOCULOFACIOSKELETAL SYNDROME 2 (1 patient)

ERCC2, ASP681ASN
  
RCV000018277...

Graham et al. (2001) described a patient with cerebrooculofacioskeletal syndrome-2 (COFS2; 610756) who was compound heterozygous for 2 mutations in the ERCC2 gene: an arg616-to-trp null mutation (R616W; 126340.0010) and a novel asp681-to-asn (D681N) mutation.


.0010 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

CEREBROOCULOFACIOSKELETAL SYNDROME 2, INCLUDED (1 patient)
ERCC2, ARG616TRP
  
RCV000018278...

Xeroderma Pigmentosum, Complementation Group D

In cell line XP1DU from a patient with xeroderma pigmentosum complementation group D (XPD; 278730), Taylor et al. (1997) identified compound heterozygous mutations in the ERCC2 gene: an arg616-to-trp substitution (R616W) and an arg683-to-trp (R683W; 126340.0015) substitution.

Cerebrooculofacioskeletal Syndrome 2

For discussion of the R616W mutation in the ERCC2 gene that was found in compound heterozygous state in a patient with cerebrooculofacioskeletal syndrome-2 (COFS2; 610756) by Graham et al. (2001), see 126340.0009.


.0011 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, 2-BP DEL, 1781TT
  
RCV000120767...

Broughton et al. (2001) described a 3-year-old girl with sun sensitivity and mental and physical developmental delay (XPD; 278730) who was compound heterozygous for mutations in the ERCC2 gene: a deletion of dinucleotide TT at 1781-1782, resulting in a frameshift and an immediate stop codon, and a complex alteration with deletion of trinucleotide AGA at 1823-1825 and insertion of TTTCGG at this site (126340.0012). The latter resulted in an in-frame alteration of codons 582 and 583 plus the addition of a glutamate residue after codon 583 adjacent to the helicase domain V.


.0012 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, 3-BP DEL/6-BP INS, NT1823
  
RCV000018281

For discussion of the ins/del mutation in the ERCC2 gene that was found in compound heterozygous state in a patient with xeroderma pigmentosum complementation group D (XPD; 278730) by Broughton et al. (2001), see 126340.0011.


.0013 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, LEU485PRO
  
RCV000018282

Broughton et al. (2001) described a 28-year-old woman with sun sensitivity, pigmentation changes, and skin cancers typical of xeroderma pigmentosum complementation group D (XPD; 278730). Mutation analysis revealed compound heterozygous mutations in the ERCC2 gene: an arg112-to-his mutation (R112H; 126340.0006), which was previously found in patients with photosensitive trichothiodystrophy, and a leu485-to-pro (L485P) mutation.


.0014 TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE

ERCC2, ARG722TRP
  
RCV000018283...

In a patient with photosensitive trichothiodystrophy-1 (TTD1; 601675), Broughton et al. (1994) found a homozygous C-to-T transition at nucleotide 2166 in the ERCC2 gene that resulted in an arg722-to-trp (R722W) amino acid substitution.


.0015 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, ARG683TRP
  
RCV000018284...

In patients with xeroderma pigmentosum complementation group D (XPD; 278730), Takayama et al. (1995) identified a C-to-T transition at nucleotide 2125 of the ERCC2 gene, resulting in an arg683-to-trp (R683W) substitution.

Drane et al. (2004) found that fibroblasts from XPD patients with the R683W mutation failed to upregulate CYP24 (CYP24A1; 126065) in response to vitamin D, whereas upregulation of osteopontin (SPP1; 166490) was normal. They demonstrated that the R683W mutation interfered with phosphorylation of ETS1 (164720) by TFIIH, which prevented binding of liganded vitamin D receptor (VDR; 601769) on the CYP24 promoter and proper assembly of the transcriptional machinery on this promoter.


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  10. Drane, P., Compe, E., Catez, P., Chymkowitch, P., Egly, J.-M. Selective regulation of vitamin D receptor-responsive genes by TFIIH. Molec. Cell 16: 187-197, 2004. [PubMed: 15494306, related citations] [Full Text]

  11. Flejter, W. L., McDaniel, L. D., Askari, M., Friedberg, E. C., Schultz, R. A. Characterization of a complex chromosomal rearrangement maps the locus for in vitro complementation of xeroderma pigmentosum group D to human chromosome band 19q13. Genes Chromosomes Cancer 5: 335-342, 1992. [PubMed: 1283322, related citations] [Full Text]

  12. Flejter, W. L., McDaniel, L. D., Johns, D., Friedberg, E. C., Schultz, R. A. Correction of xeroderma pigmentosum complementation group D mutant cell phenotypes by chromosome and gene transfer: involvement of the human ERCC2 DNA repair gene. Proc. Nat. Acad. Sci. 89: 261-265, 1992. [PubMed: 1729695, related citations] [Full Text]

  13. Frederick, G. D., Amirkhan, R. H., Schultz, R. A., Friedberg, E. C. Structural and mutational analysis of the xeroderma pigmentosum group D (XPD) gene. Hum. Molec. Genet. 3: 1783-1788, 1994. [PubMed: 7849702, related citations] [Full Text]

  14. Friedberg, E. C. Xeroderma pigmentosum, Cockayne's syndrome, helicases, and DNA repair: what's the relationship? Cell 71: 887-889, 1992. [PubMed: 1458537, related citations] [Full Text]

  15. Graham, J. M., Jr., Anyane-Yeboa, K., Raams, A., Appeldoorn, E., Kleijer, W. J., Garritsen, V. H., Busch, D., Edersheim, T. G., Jaspers, N. G. J. Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy. Am. J. Hum. Genet. 69: 291-300, 2001. [PubMed: 11443545, images, related citations] [Full Text]

  16. Hansen, L. K., Wulff, K., Brandrup, F. [Trichothiodystrophy: hair examination as a diagnostic tool]. Ugeskr. Laeger 155: 1949-1952, 1993. Note: Article in Danish. [PubMed: 8317059, related citations]

  17. Keriel, A., Stary, A., Sarasin, A., Rochette-Egly, C., Egly, J.-M. XPD mutations prevent TFIIH-dependent transactivation by nuclear receptors and phosphorylation of RAR-alpha. Cell 109: 125-135, 2002. [PubMed: 11955452, related citations] [Full Text]

  18. Kleijer, W. J., Beemer, F. A., Boom, B. W. Intermittent hair loss in a child with PIBI(D)S syndrome and trichothiodystrophy with defective DNA repair-xeroderma pigmentosum group D. Am. J. Med. Genet. 52: 227-230, 1994. [PubMed: 7802014, related citations] [Full Text]

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  20. Kobayashi, T., Uchiyama, M., Fukuro, S., Tanaka, K. Mutations in the XPD gene in xeroderma pigmentosum group D cell strains: confirmation of genotype-phenotype correlation. Am. J. Med. Genet. 110: 248-252, 2002. [PubMed: 12116233, related citations] [Full Text]

  21. Lehmann, A. R. The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev. 15: 15-23, 2001. [PubMed: 11156600, related citations] [Full Text]

  22. Liu, J., Akoulitchev, S., Weber, A., Ge, H., Chuikov, S., Libutti, D., Wang, X. W., Conaway, J. W., Harris, C. C., Conaway, R. C., Reinberg, D., Levens, D. Defective interplay of activators and repressors with TFIIH in xeroderma pigmentosum. Cell 104: 353-363, 2001. [PubMed: 11239393, related citations] [Full Text]

  23. Marinoni, S., Gaeta, G., Not, T., Freschi, P., Trevisan, G., Briscik, E., Giliani, S., et al. Early recognition of trichothiodystrophy with xeroderma pigmentosum group D mutation in a collodion baby. In: Panconesi, E. (ed.): Dermatology in Europe. Oxford: Blackwell Scientific 1991. Pp. 632-633.

  24. Mohrenweiser, H. W., Carrano, A. V., Fertitta, A., Perry, B., Thompson, L. H., Tucker, J. D., Weber, C. A. Refined mapping of the three DNA repair genes, ERCC1, ERCC2, and XRCC1, on human chromosome 19. Cytogenet. Cell Genet. 52: 11-14, 1989. [PubMed: 2558854, related citations] [Full Text]

  25. Orioli, D., Compe, E., Nardo, T., Mura, M., Giraudon, C., Botta, E., Arrigoni, L., Peverali, F. A., Egly, J. M., Stefanini, M. XPD mutations in trichothiodystrophy hamper collagen VI expression and reveal a role of TFIIH in transcription derepression. Hum. Molec. Genet. 22: 1061-1073, 2013. [PubMed: 23221806, related citations] [Full Text]

  26. Peserico, A., Battistella, P. A., Bertoli, P. MRI of a very rare hereditary ectodermal dysplasia: PIBI(D)S. Neuroradiology 34: 316-317, 1992. [PubMed: 1528442, related citations] [Full Text]

  27. Petrini, J. H. J. When more is better. Nature Genet. 26: 257-258, 2000. [PubMed: 11062454, related citations] [Full Text]

  28. Rudolf, J., Makrantoni, V., Ingledew, W. J., Stark, M. J. R., White, M. F. The DNA repair helicases XPD and FancJ have essential iron-sulfur domains. Molec. Cell 23: 801-808, 2006. [PubMed: 16973432, related citations] [Full Text]

  29. Siciliano, M. J., Carrano, A. V., Thompson, L. H. Chromosome 19 corrects two complementing DNA repair mutations present in CHO cells. (Abstract) Cytogenet. Cell Genet. 40: 744-745, 1985.

  30. Stefanini, M., Giliani, S., Nardo, T., Marinoni, S., Nazzaro, V., Rizzo, R., Trevisan, G. DNA repair investigations in nine Italian patients affected by trichothiodystrophy. Mutat. Res. 273: 119-125, 1992. [PubMed: 1372095, related citations] [Full Text]

  31. Stefanini, M., Lagomarsini, P., Giliani, S., Nardo, T., Botta, E., Peserico, A., Kleijer, W. J., Lehmann, A. R., Sarasin, A. Genetic heterogeneity of the excision repair defect associated with trichothiodystrophy. Carcinogenesis 14: 1101-1105, 1993. [PubMed: 8508495, related citations] [Full Text]

  32. Sung, P., Bailly, V., Weber, C., Thompson, L. H., Prakash, L., Prakash, S. Human xeroderma pigmentosum group D gene encodes a DNA helicase. Nature 365: 852-855, 1993. [PubMed: 8413672, related citations] [Full Text]

  33. Takayama, K., Danks, D. M., Salazar, E. P., Cleaver, J. E., Weber, C. A. DNA repair characteristics and mutations in the ERCC2 DNA repair and transcription gene in a trichothiodystrophy patient. Hum. Mutat. 9: 519-525, 1997. [PubMed: 9195225, related citations] [Full Text]

  34. Takayama, K., Salazar, E. P., Broughton, B. C., Lehmann, A. R., Sarasin, A., Thompson, L. H., Weber, C. A. Defects in the DNA repair and transcription gene ERCC2(XPD) in trichothiodystrophy. Am. J. Hum. Genet. 58: 263-270, 1996. [PubMed: 8571952, related citations]

  35. Takayama, K., Salazar, E. P., Lehmann, A., Stefanini, M., Thompson, L. H., Weber, C. A. Defects in the DNA repair and transcription gene ERCC2 in the cancer-prone disorder xeroderma pigmentosum group D. Cancer Res. 55: 5656-5663, 1995. [PubMed: 7585650, related citations]

  36. Taylor, E. M., Broughton, B. C., Botta, E., Stefanini, M., Sarasin, A., Jaspers, N. G. J., Fawcett, H., Harcourt, S. A., Arlett, C. F., Lehmann, A. R. Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD (ERCC2) repair/transcription gene. Proc. Nat. Acad. Sci. 94: 8658-8663, 1997. [PubMed: 9238033, images, related citations] [Full Text]

  37. Thompson, L. H., Brookman, K. W., Dillehay, L. E., Carrano, A. V., Mazrimas, J. A., Mooney, C. L., Minkler, J. L. A CHO-cell strain having hypersensitivity to mutagens, a defect in DNA strand-break repair, and an extraordinary baseline frequency of sister-chromatid exchange. Mutat. Res. 95: 427-440, 1982. [PubMed: 6889677, related citations] [Full Text]

  38. Vermeulen, W., Rademakers, S., Jaspers, N. G. J., Appeldoorn, E., Raams, A., Klein, B., Kleijer, W. J., Hansen, L. K., Hoeijmakers, J. H. J. A temperature-sensitive disorder in basal transcription and DNA repair in humans. Nature Genet. 27: 299-303, 2001. [PubMed: 11242112, related citations] [Full Text]

  39. Viprakasit, V., Gibbons, R. J., Broughton, B. C., Tolmie, J. L., Brown, D., Lunt, P., Winter, R. M., Marinoni, S., Stefanini, M., Brueton, L., Lehmann, A. R., Higgs, D. R. Mutations in the general transcription factor TFIIH result in beta-thalassaemia in individuals with trichothiodystrophy. Hum. Molec. Genet. 10: 2797-2802, 2001. [PubMed: 11734544, related citations] [Full Text]

  40. Weber, C. A., Salazar, E. P., Stewart, S. A., Thompson, L. H. Molecular cloning and biological characterization of a human gene, ERCC2, that corrects the nucleotide excision repair defect in CHO UV5 cells. Molec. Cell Biol. 8: 1137-1146, 1988. [PubMed: 2835663, related citations] [Full Text]

  41. Weber, C. A., Salazar, E. P., Stewart, S. A., Thompson, L. H. ERCC2: cDNA cloning and molecular characterization of a human nucleotide excision repair gene with high homology to yeast RAD3. EMBO J. 9: 1437-1447, 1990. [PubMed: 2184031, related citations] [Full Text]

  42. Yoder, K., Sarasin, A., Kraemer, K., McIlhatton, M., Bushman, F., Fishel, R. The DNA repair genes XPB and XPD defend cells from retroviral infection. Proc. Nat. Acad. Sci. 103: 4622-4627, 2006. [PubMed: 16537383, images, related citations] [Full Text]


Carol A. Bocchini - updated : 02/27/2024
Patricia A. Hartz - updated : 10/26/2016
Patricia A. Hartz - updated : 1/12/2007
Patricia A. Hartz - updated : 5/3/2006
Paul J. Converse - updated : 4/5/2006
Marla J. F. O'Neill - updated : 4/4/2006
Ada Hamosh - updated : 8/4/2003
Ada Hamosh - updated : 4/3/2003
George E. Tiller - updated : 10/15/2002
Victor A. McKusick - updated : 7/2/2002
George E. Tiller - updated : 5/13/2002
Victor A. McKusick - updated : 8/30/2001
Stylianos E. Antonarakis - updated : 3/8/2001
Victor A. McKusick - updated : 2/28/2001
Victor A. McKusick - updated : 10/27/2000
Victor A. McKusick - updated : 7/21/1999
Victor A. McKusick - updated : 10/23/1998
Victor A. McKusick - updated : 9/24/1998
Stylianos E. Antonarakis - updated : 8/3/1998
Victor A. McKusick - updated : 9/5/1997
Victor A. McKusick - updated : 6/23/1997
Creation Date:
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carol : 09/19/2022
carol : 09/17/2022
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carol : 08/09/2016
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ckniffin : 9/23/2015
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carol : 6/2/2015
carol : 5/29/2015
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carol : 5/29/2015
carol : 2/29/2012
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mgross : 6/7/2006
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carol : 4/4/2006
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terry : 8/4/2003
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cwells : 9/12/2001
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mgross : 3/8/2001
alopez : 3/8/2001
alopez : 3/1/2001
alopez : 3/1/2001
terry : 2/28/2001
alopez : 10/31/2000
terry : 10/27/2000
terry : 7/21/1999
carol : 10/26/1998
terry : 10/23/1998
alopez : 9/29/1998
carol : 9/24/1998
carol : 8/4/1998
terry : 8/3/1998
terry : 8/3/1998
terry : 9/12/1997
terry : 9/5/1997
alopez : 7/7/1997
jenny : 6/27/1997
jenny : 6/23/1997
mark : 2/21/1997
mark : 8/7/1996
terry : 8/6/1996
mark : 2/22/1996
terry : 2/19/1996
carol : 12/13/1994
mimadm : 6/25/1994
carol : 12/6/1993
carol : 1/21/1993
carol : 12/17/1992
supermim : 3/16/1992

* 126340

ERCC EXCISION REPAIR 2, TFIIH CORE COMPLEX HELICASE SUBUNIT; ERCC2


Alternative titles; symbols

EXCISION REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 2; DNA REPAIR DEFECT EM9 OF CHINESE HAMSTER OVARY CELLS, COMPLEMENTATION OF; EM9
XPD GENE; XPD


HGNC Approved Gene Symbol: ERCC2

SNOMEDCT: 68637004;  


Cytogenetic location: 19q13.32     Genomic coordinates (GRCh38): 19:45,349,837-45,370,573 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
19q13.32 ?Cerebrooculofacioskeletal syndrome 2 610756 Autosomal recessive 3
Trichothiodystrophy 1, photosensitive 601675 Autosomal recessive 3
Xeroderma pigmentosum, group D 278730 Autosomal recessive 3

TEXT

Description

ERCC2 is a subunit of the TFIIH transcription/repair factor, which functions as a DNA helicase for nucleotide excision repair (Coin et al., 1998).


Cloning and Expression

Weber et al. (1988) used the UV-sensitive Chinese hamster ovary (CHO) cell line UV5, which is defective in the incision step of nucleotide excision repair (NER), to identify and clone a complementing human gene, ERCC2.

Using a human fibroblast expression cDNA library to complement radiosensitivity in UV5 cells, followed by examining genomic DNA, Weber et al. (1990) identified full-length ERCC2. The deduced 760-amino acid protein has a calculated molecular mass of 86.9 kD. Comparison with yeast rad3 revealed a putative ATP-binding box, a DNA-binding box, and other domains common to the helicase superfamily. Within the conserved domains, ERCC2 and rad3 are 73.8% identical and 88.5% homologous. ERCC2 also has a highly basic 14-amino acid putative nuclear localization signal.


Gene Function

Flejter et al. (1992) demonstrated that the ERCC2 gene corrected the sensitivity to ultraviolet (UV) radiation and defective nucleotide excision repair in xeroderma pigmentosum cells of complementation group D (XPD; 278730). The XPD cell line used in these studies was GM08207. They first demonstrated correction by the transfer of a rearranged human chromosome by the method of microcell-mediated chromosome transfer (MMCT). Then, having demonstrated that the rearranged chromosome involved human chromosomes 16 and 19, including the region of the latter chromosome containing the ERCC2 gene, they directly transferred a cosmid containing the ERCC2 gene into XPD cells and showed that UV resistance was conferred thereby. Flejter et al. (1992) further identified a single rearranged human chromosome, designated Tneo, that corrected the UV sensitivity and excision repair defect of XPD cells in culture. They went on to analyze the complex rearrangement involving material from chromosomes 16, 17, and 19 and showed that the 19q13.2-q13.3 region was included.

The ERCC2 gene is homologous to the RAD3 gene of the budding yeast Saccharomyces cerevisiae and the Rad15+ of the fission yeast Schizosaccharomyces pombe (Friedberg, 1992). Sung et al. (1993) purified the XPD protein to near homogeneity and showed that it possesses single-stranded DNA-dependent ATPase and DNA helicase activities. Expression of the human XPD gene in S. cerevisiae complemented the lethal defect of a mutation in the RAD3 gene.

In most cases, patients with XPD and trichothiodystrophy (TTD; see 601675) carry mutations in the carboxy-terminal domain of the XPD helicase, which is one of the subunits of the transcription/repair factor TFIIH. Coin et al. (1998) demonstrated that XPD (ERCC2) interacts specifically with p44 (GTF2H2; 601748), another subunit of TFIIH, and that this interaction results in the stimulation of 5-prime-to-3-prime helicase activity. Mutations in the XPD C-terminal domain, as found in most patients, prevent the interaction with p44, thus explaining the decrease in XPD helicase activity and the NER defect.

Inherited mutations of the TFIIH helicase subunits XPB (ERCC3; 133510) or XPD yield overlapping DNA repair and transcription syndromes. The high risk of cancer in these patients is not fully explained by the repair defect. The transcription defect, however, is subtle and more difficult to evaluate. Liu et al. (2001) showed that XPB and XPD mutations block transcription activation by the FUSE-binding protein (FBP; 603444), a regulator of MYC (190080) expression, and block repression by the FBP-interacting repressor (FIR; 604819). Through TFIIH, FBP facilitates transcription until promoter escape, whereas after initiation, FIR uses TFIIH to delay promoter escape. Mutations in TFIIH that impair regulation by FBP and FIR affect proper regulation of MYC expression and have implications in the development of malignancy.

In cells derived from XPD patients, Keriel et al. (2002) observed a reduction of the ligand-dependent transactivation mediated by several nuclear receptors: retinoic acid receptor-alpha (RARA; 180240), estrogen receptor-alpha (133430), and androgen receptor (313700). They demonstrated that the XPD mutation alters cyclin-dependent kinase-7 (CDK7; 601955) function in RARA phosphorylation. Transactivation was restored upon overexpression of either wildtype XPD or RARA containing a ser77-to-glu (S77E) mutation, which mimics phosphorylated RARA. Thus, the authors demonstrated that the CDK7 kinase of TFIIH phosphorylates the nuclear receptor, allowing ligand-dependent control of the activation of the hormone-responsive genes.

The CDK-activating kinase, or CAK complex, consists of CDK7 cyclin H (CCNH; 601953) and MAT1 (MNAT1; 602659). As the kinase subunit of TFIIH, CDK7 participates in basal transcription by phosphorylating the carboxy-terminal domain of the largest subunit of RNA polymerase II. As part of CAK, CDK7 also phosphorylates other CDKs, an essential step for their activation. Chen et al. (2003) showed that the Drosophila TFIIH component Xpd, whose human homolog is ERCC2, negatively regulates the cell cycle function of Cdk7, the CAK activity. Excess Xpd titrated CAK activity, resulting in decreased Cdk T-loop phosphorylation, mitotic defects, and lethality, whereas a decrease in Xpd resulted in increased CAK activity and cell proliferation. Moreover, Chen et al. (2003) showed that Xpd is downregulated at the beginning of mitosis when Cdk1 (116940), a cell cycle target of Cdk7, is most active. Downregulation of Xpd thus seems to contribute to the upregulation of mitotic CAK activity and to regulate mitotic progression positively. Chen et al. (2003) concluded that the downregulation of Xpd might be a major mechanism of mitotic silencing of basal transcription.

Yoder et al. (2006) showed that transduction by human immunodeficiency virus (HIV) or Moloney murine leukemia virus was substantially greater in XPB or XPD mutant cells than in isogenic complemented cells or XPA (611153) mutant cells. The difference in transduction efficiency was not due to apoptosis. Yoder et al. (2006) concluded that XPB and XPD reduce retroviral integration efficiency by enhancing degradation of retroviral cDNA, thereby reducing the available pool of cDNA molecules for integration.

Rudolf et al. (2006) identified a conserved domain that includes an iron-sulfur (Fe-S) cluster near the N termini of XPD and FANCJ (BRIP1; 605882). Three absolutely conserved cysteines provide ligands for the Fe-S cluster, and Rudolf et al. (2006) showed that the cluster is essential for XPD helicase activity. Yeast strains harboring mutations in the Fe-S domain of Rad3 retained their overall fold and stability and could hydrolyze ATP in a single-stranded DNA-dependent manner, but they were defective in nucleotide excision repair of UV-induced damage.

Orioli et al. (2013) found that skin of TTD patients with mutations in the ERCC2 gene had reduced content of COL6A1 (120220), an abundant collagen of skin and connective tissue. In culture, dermal fibroblasts from TTD patients failed to induce COL6A1 upon achieving confluence. XPD skin and cultured XPD fibroblasts with mutations in the ERCC2 gene did not show the same defects. Transfection of wildtype ERCC2 into TTD patient fibroblasts permitted induction of COL6A1 upon confluence. In silico analysis identified a putative SREBP1 (184756)-binding site in the COL6A1 promoter, and deletion of this site resulted in increased transcriptional activity from the COL6A1 promoter. Overexpression of wildtype ERCC2 in TTD patient fibroblasts resulted in RNA polymerase II and SP1 (189906) occupancy at the COL6A1 promoter, concomitant with loss of SREBP1 binding. Removal of SREBP1 from the COL6A1 promoter was also dependent on ATP hydrolysis. Orioli et al. (2013) concluded that ERCC2 in the TFIIH helicase removes SREBP1 from the COL6A1 promoter in an ATP-dependent manner and that, in TTD fibroblasts, mutated ERCC2 fails to displace the SREBP1 repressor from the COL6A1 promoter, resulting in inability to effect COL6A1 transcriptional upregulation in response to cell confluence.


Gene Structure

Frederick et al. (1994) characterized the genomic structure of the XPD (ERCC2) gene and found that it contains 23 exons ranging in size from 5 bp (exon 1) to 169 bp (exon 11).

Weber et al. (1990) determined that the 5-prime flanking region of the ERCC2 gene contains a classical TATA box, a reverse CAAT box, and a GC box. It also has a 34-base pyrimidine-rich region and a 12-base inverted repeat with 2 central bases of noncomplementarity.


Mapping

By somatic cell hybridization, Siciliano et al. (1985) assigned to human chromosome 19 a gene that complements a DNA repair defect in Chinese hamster ovary (CHO) cells called EM9. A second DNA repair defect of CHO cells, UV20 (ERCC1; 126380), was likewise corrected by human chromosome 19, which appears to be homologous to hamster chromosome 9; both contain GPI (172400) and PEPD (613230). In CHO cells, chromosome 9 is hemizygous. Thus, the findings probably indicate that 2 DNA repair genes are part of the homologous synteny group in these 2 species. By large fragment restriction enzyme site mapping, Mohrenweiser et al. (1989) found that ERCC1 and ERCC2 are separated by less than 250 kb. Greatly increased sister chromatid exchanges are characteristic of EM9 cells (Thompson et al., 1982), as in Bloom syndrome (210900).


Molecular Genetics

In cell lines from patients with xeroderma pigmentosum group D (XPD; 278730), Frederick et al. (1994) identified mutations in the ERCC2 gene (126340.0001-126340.0002).

Botta et al. (1998) determined the mutations and the pattern of inheritance of the XPD alleles in 11 patients with trichothiodystrophy identified in Italy. In all of the patients, the hair abnormalities diagnostic for TTD were associated with different disease severity but similar cellular photosensitivity. They identified 8 causative mutations, 4 of which had not previously been described, either in TTD or XP cases, supporting their hypothesis that the mutations responsible for TTD are different from those found in other pathologic phenotypes. The arg112-to-his (R112H; 126340.0006) mutation was the most common one found in the Italian patients, 5 of whom were homozygous and 2 heterozygous, for this mutation. Patients with this mutation had been reported by Battistella and Peserico (1996), Marinoni et al. (1991), Stefanini et al. (1992), Peserico et al. (1992), and Stefanini et al. (1993). Microscopic study of the hair showed pili torti, trichoschisis, and trichorrhexis nodosa. Polarization microscopy revealed a typical appearance of alternating light and dark bands, giving a 'tiger tail' pattern. Photosensitivity was reported in all patients, in association with the other symptoms typical of TTD, namely, ichthyosis, delayed physical and mental development, nail dysplasia, a face characterized by receding chin, small nose, and large ears, and microcephaly. Seven patients were still alive at ages 4 to 30 years; the 4 patients who died during early infancy showed severe physical and mental retardation and suffered from frequent respiratory infections. The 3 oldest patients, all women, aged 30, 20, and 21 years, had moderate mental and physical handicaps. They developed freckles during childhood, but progression to malignancy had not been observed. They had short stature (140 cm), began to menstruate at age 18 years, and were no longer prone to infections, although they suffered moderate infections during early childhood.

Kleijer et al. (1994) described a trichothiodystrophy patient (TTD1RO) with unusual additional features: during repeated episodes of pneumonia, she lost all her 'brittle' hair in 1 or 2 days, though it did regrow to the usual length after recovery. Concomitantly, her skin symptoms showed a transient, reversible deterioration. The patient was found by Takayama et al. (1996) to carry 2 unique point mutations in XPD: an arg658-to-cys (R658C; 126340.0007) amino acid substitution on one allele and a gly713-to-arg (G713R; 126340.0008) change on the other. In a screening of various TTD cases, Vermeulen et al. (2001) detected the R658C mutation in a female patient (TTD1DOD) of different ethnic background who was previously reported by Hansen et al. (1993). In conditions of high fever, she also exhibited unusual sudden hair loss, and her signs of ataxia were transiently aggravated. An affected brother and a patient from a related family showed the same manifestations. Thus, the R658C change was the phenotype-determining allele. Vermeulen et al. (2001) found that cells from these patients show an in vivo temperature-sensitive defect of transcription and DNA repair due to thermoinstability of TFIIH. Vermeulen et al. (2001) noted that temperature-sensitive mutations with manifestations associated with fever have been described rarely: see, e.g., hemoglobin Zurich (141900.0310) and antithrombin-III Rouen VI (107300.0046).

Broughton et al. (2001) identified 2 patients with some features of both XP and TTD. A 3-year-old girl with sun sensitivity and mental and physical developmental delay was compound heterozygous for mutations in the ERCC2 gene (126340.0011-126340.0012). Cultured cells from this patient demonstrated barely detectable levels of nucleotide excision repair. The other patient, a 28-year-old woman with sun sensitivity, pigmentation changes, and skin cancers typical of XP, had an arg112-to-his mutation (R112H; 126340.0006), seen previously in TTD patients, on one allele and a leu485-to-pro mutation (L485P; 126340.0013) on the other allele. The level of UV damage repair in the second patient was substantially higher than that in other patients with the same mutation. In both patients, polarized light microscopy revealed a tiger-tail appearance of the hair, and amino acid analysis of the hairshafts showed levels of sulfur-containing proteins between those of normal and TTD individuals.

Graham et al. (2001) reported involvement of the ERCC2 gene in a case of UV-sensitive COFS syndrome (214150), with compound heterozygosity for an arg616-to-trp null mutation (R616W; 126340.0010), previously found in a patient with XPD by Taylor et al. (1997), and a novel asp681-to-asn mutation (D681N; 126340.0009). They demonstrated, in a triplet pregnancy and in a subsequent singleton pregnancy, how the findings of abnormal DNA repair could be used for prenatal diagnosis of COFS syndrome.

In 5 XPD cell strains tested, Kobayashi et al. (2002) identified 6 positive disease-causing mutations in the ERCC2 gene. Each cell line was a compound heterozygote with different mutations. In each, 1 allele was thought to be functionally null and the other was a less severe allele with 3 mutations. The second allele in each strain was specific to the XP phenotype. Kobayashi et al. (2002) interpreted the results as consistent with the hypothesis that the site of mutation in the ERCC2 gene determines the clinical phenotype, XP or TTD.

Viprakasit et al. (2001) showed that the specific mutations in the ERCC2 gene that cause TTD result in reduced expression of the beta-globin (HBB; 141900) genes in these individuals. Eleven TTD patients with characterized mutations in the XPD gene were found to have the hematologic features of beta-thalassemia trait, and reduced levels of beta-globin synthesis and beta-globin mRNA. All of these parameters were normal in 3 patients with XP. The authors hypothesized that many of the clinical features of TTD may result from inadequate expression of a diverse set of highly expressed genes.

Reviews

Cleaver et al. (1999) tabulated the very large number of mutations that had been identified in the XPD gene in patients with diverse phenotypes.


Genotype/Phenotype Correlations

Taylor et al. (1997) identified the mutations in a large group of TTD and XPD patients to determine if the clinical phenotypes of XP and TTD could be attributed to the sites of the mutations. Most sites of mutations differed between XP and TTD, but there were 3 sites at which the same mutation was found in XP and TTD patients. Since the corresponding patients were all compound heterozygotes with different mutations in the 2 alleles, the alleles were tested separately in a yeast complementation assay. The mutations that were found in both XP and TTD patients behaved as null alleles, suggesting that the disease phenotype was determined by the other allele. When Taylor et al. (1997) eliminated the null mutations, the remaining mutagenic pattern was consistent with the site of the mutation determining the phenotype. Changes at arg683 were clearly associated with XP, whereas arg112his, arg722trp, and changes at arg658 appeared to be associated with TTD. They cited unpublished observations of a TTD patient of Turkish origin who was homozygous for the arg658cys change previously found in 1 allele of a TTD patient, suggesting that this allele is sufficient for the TTD phenotype. The 6 mutational changes of arginine residues observed at these 4 sites were all C-to-T or G-to-A mutations at CpG sites, which are presumed to result from deamination of 5-methylcytosine to thymine.

Petrini (2000) and Lehmann (2001) noted that the diversity of clinical outcomes associated with XPD and XPB mutations appeared to be explained by allele-specific mutations.


Animal Model

De Boer et al. (1998) generated a mouse model for trichothiodystrophy by gene-cDNA fusion targeting and introduction of the ERCC2/XPD arg722-to-trp (R722W; 126340.0014) mutation in the mouse, thereby mimicking the causative XPD point mutation of a TTD patient. TTD R722W/R722W mice reflect to a remarkable extent the human disorder, including brittle hair, developmental abnormalities, reduced life span, UV sensitivity, and skin abnormalities. The cutaneous symptoms are associated with reduced transcription of a skin-specific gene, SPRR2 (182267), strongly supporting the concept of TTD as a human disease due to inborn defects in basal transcription and DNA repair.

De Boer et al. (2002) found that mice with the R722W mutation in ERCC2 had many symptoms of premature aging, including osteoporosis and kyphosis, osteosclerosis, early graying, cachexia, infertility, and reduced life span. TTD mice carrying an additional mutation in XPA, which enhances the DNA repair defect, showed a greatly accelerated aging phenotype, which correlated with an increased cellular sensitivity to oxidative DNA damage. De Boer et al. (2002) hypothesized that aging in TTD mice is caused by unrepaired DNA damage that compromises transcription, leading to functional inactivation of critical genes and enhanced apoptosis.


ALLELIC VARIANTS 15 Selected Examples):

.0001   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE, INCLUDED
ERCC2, LEU461VAL
SNP: rs121913016, gnomAD: rs121913016, ClinVar: RCV000018267, RCV000120764, RCV000171546, RCV000897210, RCV002256001, RCV002513097, RCV003123387

Xeroderma Pigmentosum, Complementation Group D

In cell line GM436 from a patient with xeroderma pigmentosum complementation group D (XPD; 278730), Frederick et al. (1994) identified a 1411C-G transversion in the ERCC2 gene, predicted to result in a leu461-to-val (L461V) substitution.

Trichothiodystrophy 1, Photosensitive

Takayama et al. (1997) studied a male patient with typical features of trichothiodystrophy (TTD1; 601675), including brittle hair, ichthyosis, characteristic face with receding chin and protruding ears, sun sensitivity, and mental and growth retardation. The relative amount of nucleotide excision repair (NER) carried out by a fibroblast cell strain from the patient after ultraviolet exposure was approximately 65% of normal as determined by a method that converted repair patches into quantifiable DNA breaks. UV survival curves showed a reduction in survival only at doses greater than 4 joules per square meter. Sequence analysis of the ERCC2 gene showed a leu461-to-val (L461V; 126340.0001) substitution and a deletion of amino acids 716-730 on one allele and an ala725-to-pro (A725P; 126340.0003) substitution on the other allele. The L461V mutation had been reported in a patient with xeroderma pigmentosum group D by Frederick et al. (1994) and in 2 other trichothiodystrophy patients (see Takayama et al., 1996), whereas the A725P mutation had not previously been reported. Comparisons suggested that the A725P mutation correlated with TTD with intermediate UV sensitivity.


.0002   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, GLN726TER
SNP: rs121913017, gnomAD: rs121913017, ClinVar: RCV000018269

In cell line XP67MA from a patient with xeroderma pigmentosum complementation group D (XPD; 278730), Frederick et al. (1994) identified a 2176C-T transition in exon 22 of the ERCC2 gene, changing codon 726 from CAG (gln) to TAG (stop). The mutation was predicted to produce a protein truncated by 34 amino acids. Although expression of the normal XPD cDNA could be shown to correct the UV sensitivity phenotype in XPD cells, cDNA constructs bearing either this or the L461V mutation (126340.0001) failed to yield complementation.


.0003   TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE

ERCC2, ALA725PRO
SNP: rs121913018, gnomAD: rs121913018, ClinVar: RCV000018270, RCV001851906, RCV002490383, RCV003155035, RCV003343601, RCV003460482

For discussion of the ala725-to-pro (A725P) mutation in the ERCC2 gene that was found in compound heterozygous state in a patient with photosensitive trichothiodystrophy (TTD1; 601675) by Takayama et al. (1997), see 126340.0001.


.0004   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, 4-BP DEL, NT668
SNP: rs767747355, gnomAD: rs767747355, ClinVar: RCV002266015, RCV003464133, RCV003560844

Kobayashi et al. (1997) reported 2 causative mutations of the XPD gene in a Japanese patient with xeroderma pigmentosum complementation group D (XPD; 278730) and only mild skin symptoms of the disorder, without Cockayne syndrome, trichothiodystrophy, or other neurologic complications. One of the mutations in this compound heterozygote was a 4-bp deletion at nucleotides 668 to 671, resulting in frameshift and premature termination. The other was a nucleotide substitution leading to conversion of serine-541 to arginine (S541R; 126340.0005) in helicase domain IV of the XPD protein. The patient's father was heterozygous for the deletion, whereas the mother was heterozygous for the S541R mutation. An expression study showed that the XPD cDNA containing the deletion or the S541R missense mutation failed to restore UV sensitivity of XPD cells, whereas the wildtype XPD cDNA restored it to the normal level.


.0005   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, SER541ARG
SNP: rs121913019, gnomAD: rs121913019, ClinVar: RCV000018272

For discussion of the ser541-to-arg (S541R) mutation in the XPD gene that was found in compound heterozygous state in a patient with xeroderma pigmentosum complementation group D (XPD; 278730) by Kobayashi et al. (1997), see 126340.0004.


.0006   TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE

XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D, INCLUDED
ERCC2, ARG112HIS
SNP: rs121913020, gnomAD: rs121913020, ClinVar: RCV000018273, RCV000018274, RCV000424822, RCV003466865

Trichothiodystrophy 1, Photosensitive

Of 11 reported Italian patients with photosensitive trichothiodystrophy-1 (TTD1; 601675), Botta et al. (1998) noted that 5 were homozygous for an arg112-to-his (R112H) mutation in the ERCC2 gene and 2 were compound heterozygous.

Xeroderma Pigmentosum, Complementation Group D

Broughton et al. (2001) described a 28-year-old woman with sun sensitivity, pigmentation changes, and skin cancers typical of xeroderma pigmentosum complementation group D (XPD; 278730). Mutation analysis revealed compound heterozygous mutations in the ERCC2 gene: the R112H mutation and a leu485-to-pro (L485P; 126340.0003) substitution.


.0007   TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE

ERCC2, ARG658CYS
SNP: rs121913021, gnomAD: rs121913021, ClinVar: RCV000018275, RCV002482884, RCV002513098, RCV003153304, RCV003460483

In a girl with photosensitive trichothiodystrophy-1 (TTD1; 601675), Takayama et al. (1996) found a C-to-T transition at nucleotide position 2050 of the ERCC2 gene, resulting in an arg658-to-cys amino acid change (R658C). The causative mutation on the other allele was identified as gly713-to-arg (G713R; 126340.0008). Ichthyosis and loss of scalp hair occurred intermittently in the patient.

In 2 patients with trichothiodystrophy with the unusual additional feature of aggravation during fever, Vermeulen et al. (2001) found an R658C mutation in the ERCC2 gene.


.0008   TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE

ERCC2, GLY713ARG
SNP: rs121913022, ClinVar: RCV000018276, RCV003230368

In a girl with photosensitive trichothiodystrophy-1 (TTD1; 601675), Takayama et al. (1996) found a G-to-C transversion at nucleotide position 2215 of the ERCC2 gene, resulting in a gly713-to-arg amino acid substitution. They identified this mutation in compound heterozygous state with R658C (126340.0007).


.0009   CEREBROOCULOFACIOSKELETAL SYNDROME 2 (1 patient)

ERCC2, ASP681ASN
SNP: rs121913023, gnomAD: rs121913023, ClinVar: RCV000018277, RCV003114198, RCV003488344

Graham et al. (2001) described a patient with cerebrooculofacioskeletal syndrome-2 (COFS2; 610756) who was compound heterozygous for 2 mutations in the ERCC2 gene: an arg616-to-trp null mutation (R616W; 126340.0010) and a novel asp681-to-asn (D681N) mutation.


.0010   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

CEREBROOCULOFACIOSKELETAL SYNDROME 2, INCLUDED (1 patient)
ERCC2, ARG616TRP
SNP: rs121913024, gnomAD: rs121913024, ClinVar: RCV000018278, RCV000171547, RCV001582486, RCV002468972

Xeroderma Pigmentosum, Complementation Group D

In cell line XP1DU from a patient with xeroderma pigmentosum complementation group D (XPD; 278730), Taylor et al. (1997) identified compound heterozygous mutations in the ERCC2 gene: an arg616-to-trp substitution (R616W) and an arg683-to-trp (R683W; 126340.0015) substitution.

Cerebrooculofacioskeletal Syndrome 2

For discussion of the R616W mutation in the ERCC2 gene that was found in compound heterozygous state in a patient with cerebrooculofacioskeletal syndrome-2 (COFS2; 610756) by Graham et al. (2001), see 126340.0009.


.0011   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, 2-BP DEL, 1781TT
SNP: rs587778271, gnomAD: rs587778271, ClinVar: RCV000120767, RCV000778548, RCV001008079, RCV002498561, RCV003230409, RCV003343649, RCV003407511, RCV003444202, RCV003467077

Broughton et al. (2001) described a 3-year-old girl with sun sensitivity and mental and physical developmental delay (XPD; 278730) who was compound heterozygous for mutations in the ERCC2 gene: a deletion of dinucleotide TT at 1781-1782, resulting in a frameshift and an immediate stop codon, and a complex alteration with deletion of trinucleotide AGA at 1823-1825 and insertion of TTTCGG at this site (126340.0012). The latter resulted in an in-frame alteration of codons 582 and 583 plus the addition of a glutamate residue after codon 583 adjacent to the helicase domain V.


.0012   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, 3-BP DEL/6-BP INS, NT1823
SNP: rs2123229159, ClinVar: RCV000018281

For discussion of the ins/del mutation in the ERCC2 gene that was found in compound heterozygous state in a patient with xeroderma pigmentosum complementation group D (XPD; 278730) by Broughton et al. (2001), see 126340.0011.


.0013   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, LEU485PRO
SNP: rs121913025, ClinVar: RCV000018282

Broughton et al. (2001) described a 28-year-old woman with sun sensitivity, pigmentation changes, and skin cancers typical of xeroderma pigmentosum complementation group D (XPD; 278730). Mutation analysis revealed compound heterozygous mutations in the ERCC2 gene: an arg112-to-his mutation (R112H; 126340.0006), which was previously found in patients with photosensitive trichothiodystrophy, and a leu485-to-pro (L485P) mutation.


.0014   TRICHOTHIODYSTROPHY 1, PHOTOSENSITIVE

ERCC2, ARG722TRP
SNP: rs121913026, gnomAD: rs121913026, ClinVar: RCV000018283, RCV000255624, RCV000677676, RCV000763052, RCV001199920, RCV001265586, RCV001449816, RCV003398537

In a patient with photosensitive trichothiodystrophy-1 (TTD1; 601675), Broughton et al. (1994) found a homozygous C-to-T transition at nucleotide 2166 in the ERCC2 gene that resulted in an arg722-to-trp (R722W) amino acid substitution.


.0015   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D

ERCC2, ARG683TRP
SNP: rs41556519, gnomAD: rs41556519, ClinVar: RCV000018284, RCV000518900, RCV000623275, RCV000763053, RCV003460484

In patients with xeroderma pigmentosum complementation group D (XPD; 278730), Takayama et al. (1995) identified a C-to-T transition at nucleotide 2125 of the ERCC2 gene, resulting in an arg683-to-trp (R683W) substitution.

Drane et al. (2004) found that fibroblasts from XPD patients with the R683W mutation failed to upregulate CYP24 (CYP24A1; 126065) in response to vitamin D, whereas upregulation of osteopontin (SPP1; 166490) was normal. They demonstrated that the R683W mutation interfered with phosphorylation of ETS1 (164720) by TFIIH, which prevented binding of liganded vitamin D receptor (VDR; 601769) on the CYP24 promoter and proper assembly of the transcriptional machinery on this promoter.


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Contributors:
Carol A. Bocchini - updated : 02/27/2024
Patricia A. Hartz - updated : 10/26/2016
Patricia A. Hartz - updated : 1/12/2007
Patricia A. Hartz - updated : 5/3/2006
Paul J. Converse - updated : 4/5/2006
Marla J. F. O'Neill - updated : 4/4/2006
Ada Hamosh - updated : 8/4/2003
Ada Hamosh - updated : 4/3/2003
George E. Tiller - updated : 10/15/2002
Victor A. McKusick - updated : 7/2/2002
George E. Tiller - updated : 5/13/2002
Victor A. McKusick - updated : 8/30/2001
Stylianos E. Antonarakis - updated : 3/8/2001
Victor A. McKusick - updated : 2/28/2001
Victor A. McKusick - updated : 10/27/2000
Victor A. McKusick - updated : 7/21/1999
Victor A. McKusick - updated : 10/23/1998
Victor A. McKusick - updated : 9/24/1998
Stylianos E. Antonarakis - updated : 8/3/1998
Victor A. McKusick - updated : 9/5/1997
Victor A. McKusick - updated : 6/23/1997

Creation Date:
Victor A. McKusick : 6/4/1986

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