Alternative titles; symbols
HGNC Approved Gene Symbol: ERCC3
Cytogenetic location: 2q14.3 Genomic coordinates (GRCh38) : 2:127,257,290-127,294,144 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q14.3 | Trichothiodystrophy 2, photosensitive | 616390 | Autosomal recessive | 3 |
| Xeroderma pigmentosum, group B | 610651 | Autosomal recessive | 3 |
The human genes correcting the rodent repair defects are termed excision repair cross-complementing, or ERCC, genes. A number appended to the symbol refers to the rodent complementary group that is corrected by the human gene. The human ERCC3 gene product specifically corrects the defect in an early step of the DNA nucleotide excision repair (NER) pathway of UV-sensitive rodent mutants of complementation group 3. See also ERCC1 (126380), ERCC2 (126340), ERCC4 (133520), ERCC5 (133530), and ERCC6 (609413), as well as the XRCC1 (194360) gene that corrects the x-ray sensitivity of the Chinese hamster ovary (CHO) mutant cell line EM9.
Weeda et al. (1990) cloned the ERCC3 gene after DNA-mediated gene transfer of HeLa chromosomal DNA into a UV-sensitive CHO mutant in complementation group 3. The deduced 782-residue protein contains several conserved DNA-binding domains, strongly suggesting that it is a DNA repair helicase.
Mounkes et al. (1992) demonstrated that the 'haywire' gene of Drosophila encodes a protein with 66% identity to the product of the human ERCC3 gene. Park et al. (1992) identified a yeast homolog of human ERCC3, which they termed RAD25, or SSL2. The RAD25 gene encodes an 843-amino acid protein that shares 55% identical and 72% conserved amino acid residues with the human protein. The 2 proteins resemble one another in containing the conserved DNA helicase sequence motifs.
Weeda et al. (1991) determined that the human ERCC3 gene contains 14 exons and spans approximately 45 kb. The donor splice site of the third exon contains a GC instead of the canonical GT dinucleotide. The promoter region, first exon, and first intron comprise a CpG island with several putative GC boxes.
Using cell hybridization, Siciliano et al. (1987) and Thompson et al. (1987) mapped the ERCC3 gene to chromosome 2q23-qter.
Weeda et al. (1991) assigned the ERCC3 gene to 2q21 by use of somatic cell hybrids containing a translocated chromosome 2 and by in situ hybridization with fluorescently labeled ERCC3 probes.
The XPB gene product is a subunit of the general transcription factor IIH (TFIIH). Weeda et al. (1997) presented evidence that both XPB and XPD (ERCC2; 126340) have dual roles in 2 distinct metabolic processes: DNA repair and transcription.
In a yeast homolog of human ERCC3, Park et al. (1992) found that a nonsense mutation at codon 799 in RAD25 that deleted the 45 C-terminal amino acid residues conferred UV sensitivity. This mutation showed epistasis in relation to genes in the excision repair group, whereas a synergistic increase in UV sensitivity occurred when it was combined with mutations in genes in other DNA repair pathways, indicating that RAD25 functions in excision repair, but not in other repair, pathways. Park et al. (1992) also showed that RAD25 is an essential gene; a mutation of the lys392 residue to arginine was lethal. Guzder et al. (1994) showed that purified RAD25 protein from Saccharomyces cerevisiae contains single-stranded DNA-dependent ATPase and DNA helicase activities. Extract from a conditional lethal mutant exhibited a thermolabile transcriptional defect that could be corrected by the addition of RAD25, indicating a direct and essential role of that protein in RNA polymerase II transcription. Study of other mutants in which Guzder et al. (1994) could separate RAD25 DNA-repair activity from its transcription function suggested that the RAD25-encoded DNA helicase functions in DNA duplex opening during transcription initiation.
Schaeffer et al. (1993) identified the ERCC3 gene product as one of the components of the human transcription factor BTF2/TFIIH required for a late step in the initiation of transcription of genes with the class II promoter. ERCC3 is also a DNA repair helicase. The findings of Schaeffer et al. (1993) indicated that transcription and nucleotide excision repair share common factors and hence may be considered to be functionally related.
Kim et al. (2000) demonstrated that the TFIIH ERCC3 subunit, the DNA helicase responsible for ATP-dependent promoter melting during transcription initiation, does not interact with the promoter region that undergoes melting but instead interacts with DNA downstream of this region. Kim et al. (2000) also demonstrated that promoter melting does not change protein-DNA interactions upstream of the region that undergoes melting, but does change interactions within and downstream of this region. Kim et al. (2000) concluded that their results rule out the proposal that TFIIH functions in promoter melting through a conventional DNA helicase mechanism; they proposed a new model wherein TFIIH functions as a molecular wrench rotating downstream DNA relative to fixed upstream protein-DNA interactions, thereby generating torque on, and melting, the intervening DNA.
Inherited mutations of the TFIIH helicase subunits XPB or XPD yield overlapping DNA repair and transcription syndromes with increased risk of cancer (see 610651 and 278730, respectively). Clinical features attributed to the transcription defect, however, are subtle and 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.
The Rift Valley fever virus (RVFV) is the causative agent of fatal hemorrhagic fever in humans and acute hepatitis in ruminants. Le May et al. (2004) found that infection by RVFV led to a rapid and drastic suppression of host cellular RNA synthesis that paralleled a decrease of the TFIIH transcription factor cellular concentration. The nonstructural viral NSs protein interacted with the p44 component of TFIIH (GTF2H2; 601748) to form nuclear filamentous structures that also contained the XPB subunit of TFIIH. By competing with XPD, the natural partner of p44 within TFIIH, and sequestering p44 and XPB subunits, NSs prevented the assembly of TFIIH subunits, thus destabilizing the normal host cell life. These observations shed light on the mechanism utilized by RVFV to evade the host response.
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 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.
Coin et al. (2007) found that XPB interacts with the TFIIH p52 subunit (GTF2H4; 601760) and that the interaction stimulates the ATPase activity of XPB. In vitro studies showed that the TFIIH from an XPB patient with the F99S mutation (133510.0002) was unable to induce the opening of DNA around lesions, due to the incorrect XPB/p52 interaction and lack of ATPase stimulation. Further studies with recombinant mutant XPB proteins showed that the helicase activity of XPB was dispensable for nucleotide excision repair, but its ATPase activity in combination with the helicase activity of XPD was required.
Xeroderma Pigmentosum Complementation Group B/Cockayne Syndrome
In a woman with type B xeroderma pigmentosum/Cockayne syndrome (610651), originally reported by Robbins et al. (1974), Weeda et al. (1990) identified a heterozygous mutation in the ERCC3 gene (133510.0001). Oh et al. (2006) identified a second mutant allele (133510.0005) in this patient.
In 2 brothers with XPB/Cockayne syndrome (Scott et al., 1993), Vermeulen et al. (1994) identified a heterozygous mutation in the ERCC3 gene (F99S; 133510.0002). Oh et al. (2006) identified a second pathogenic mutation (133510.0008) in these patients.
Cleaver et al. (1999) reviewed the 3 ERCC3 mutations that had been identified in association with XPB.
In 2 unrelated patients from Slovenia and Germany, respectively, with severe forms of XPB/Cockayne syndrome with skin and neurologic manifestations, Oh et al. (2006) identified compound heterozygosity for 2 mutations in the ERCC3 gene (133510.0001 and 133510.0006 or 133510.0007).
Trichothiodystrophy 2, Photosensitive
Weeda et al. (1997) characterized the nucleotide excision repair defect in 2 patients with a mild form of trichothiodystrophy (TTD2; 616390) and confirmed the assignment of these cases to the complementation group B of XP. The causative mutation was found to be a single base substitution causing a missense mutation (T119P; 133510.0003) in a region of the XPB protein completely conserved in yeast, Drosophila, and human.
Ercc3-deficient rodent mutants phenotypically resemble human xeroderma pigmentosum (Weeda et al., 1990).
In a woman with type B xeroderma pigmentosum/Cockayne syndrome (610651) reported by Robbins et al. (1974), Weeda et al. (1990) identified a heterozygous C-to-A transversion in the splice acceptor sequence of intron 14 of the only ERCC3 allele that was detectably expressed. Whereas the RNA of the patient showed clear hybridization only with a mutant-specific probe, the RNA from her mother showed clear hybridization with both the mutant and wildtype probes. This patient was the first identified with complementation group B xeroderma pigmentosum.
Hwang et al. (1996) performed detailed in vitro studies of the mutant XPB protein identified by Weeda et al. (1990). As the XPB protein is a subunit of the generalized transcription factor IIH, mutant GTF2H1 (189972) isolated from the patient showed decreased 3-prime to 5-prime XPB helicase activity and decreased DNA-dependent ATPase activities, resulting in a severe DNA nucleotide excision repair (NER) defect (5-10% of wildtype). There was also evidence for a decrease in basal transcription activity. The patient had combined clinical signs of XP and Cockayne syndrome, which Hwang et al. (1996) concluded was consistent with a combined defect in DNA repair and transcription. The typical XP features, such as sun sensitivity, pigmentation abnormalities, and cancer predisposition, were consistent with a defect in NER, whereas dwarfism, neuromyelination defects, deafness, and impaired sexual development may have resulted from decreased transcription.
Oh et al. (2006) identified heterozygosity for the IVS14AS-6C-A transversion in 2 unrelated patients from Slovenia and Germany, respectively, with severe forms of XPB/Cockayne syndrome with skin and neurologic manifestations. They also confirmed heterozygosity for the mutation in the original patient reported by Robbins et al. (1974) and Weeda et al. (1990). Additional genetic analysis found that all 3 patients were compound heterozygous for the splice site mutation and another pathogenic ERCC3 mutation resulting in truncated proteins (see 133510.0005; 133510.0006; 133510.0007).
In 2 brothers with xeroderma pigmentosum type B/Cockayne syndrome (610651) reported by Scott et al. (1993), Vermeulen et al. (1994) identified a heterozygous mutation in the ERCC3 gene, resulting in a phe99-to-ser (F99S) substitution in a highly conserved region of the ERCC3 protein. Phenylalanine is a consistent finding at position 99 with aspartic acid at position 98 and leucine at position 100 in human, mouse, Drosophila, and yeast. Despite equally severe deficiency of nucleotide excision repair as measured in fibroblasts, the patients were much less severely affected than the original patient of Robbins et al. (1974) (see 133510.0001). Oh et al. (2006) identified a second pathogenic ERCC3 mutation (133510.0008) in these brothers.
In 2 sisters with a relatively mild form of XP without major features of Cockayne syndrome, Oh et al. (2006) identified compound heterozygosity for 2 mutations in the ERCC3 gene: a 296T-C transition in exon 3 of the ERCC3 gene, resulting in an F99S substitution, and R425X (133510.0004). Both patients had XP features of sun sensitivity and freckle-like pigmentation, multiple basal cell carcinomas, and ocular malignant melanomas. The only neurologic signs were childhood-onset progressive sensorineural deafness in both and mild cerebellar ataxia in 1. Each parent was heterozygous for 1 of the mutations. Both sisters gave birth to healthy children. Studies of patient-derived cells showed decreased DNA repair rates and decreased levels of XPB protein. Oh et al. (2006) noted the relatively mild phenotype associated with this mutation.
In 2 sibs, born of consanguineous parents, with photosensitive trichothiodystrophy-2 (TTD2; 616390), Weeda et al. (1997) identified a homozygous thr119-to-pro (T119P) substitution in the ERCC3 gene. The proband, a male, had congenital ichthyosis (collodion baby). The skin condition improved within 3 weeks, leaving a mild ichthyosis of the trunk. TTD was suspected at 3 years of age, on the basis of mild ichthyosis of the trunk, with involvement of the scalp, palms, and soles; mild photosensitivity; lack of second upper incisor; and hair that grew normally but was coarse, with a tiger-tail pattern under polarized light. The diagnosis of TTD was confirmed by analysis of the amino acid content of hair, showing a decrease in cysteine residues. An older affected sister had a similar presentation as a collodion baby with favorable outcome. A diagnosis of TTD was confirmed by hair microscopy and biochemical analysis showing low cysteine content. Both the proband and his sister were in good general health, without physical and mental impairment, at the ages of 10 and 16 years, respectively.
In 2 sisters with a relatively mild form of type B xeroderma pigmentosum without major manifestations of Cockayne syndrome (610651), Oh et al. (2006) identified compound heterozygosity for 2 mutations in the ERCC3 gene: a 1273C-T transition in exon 8, resulting in an arg425-to-ter (R425X) substitution, and F99S (133510.0002). Each parent was heterozygous for 1 of the mutations.
In a patient with a severe form of type B xeroderma pigmentosum/Cockayne syndrome (610651) first reported by Robbins et al. (1974), Oh et al. (2006) identified compound heterozygosity for 2 mutations in the ERCC3 gene: a splice site mutation (133510.0001) and a 2-bp deletion (807delTT). The 2-bp deletion was inherited from the patient's father.
In a patient with a severe form of type B xeroderma pigmentosum/Cockayne syndrome (610651), Oh et al. (2006) identified compound heterozygosity for 2 mutations in the ERCC3 gene: a splice site mutation (133510.0001) and a 1-bp insertion (1421insA) in exon 9, resulting in a frameshift and premature termination of the protein at codon 475.
In a patient with a severe form of type B xeroderma pigmentosum/Cockayne syndrome (610651), Oh et al. (2006) identified compound heterozygosity for 2 mutations in the ERCC3 gene: a splice site mutation (133510.0001) and a 1633C-T transition in exon 10, resulting in a gln545-to-ter (Q545X) substitution.
In 2 adult brothers with type B xeroderma pigmentosum/Cockayne syndrome (610651), Oh et al. (2006) identified a heterozygous G-to-A transition at the +1 position of intron 3 (IVS3DS+1G-A) of the ERCC3 gene, resulting in premature termination of the protein at codon 162. The mother also carried the mutation. These brothers had been shown by Vermeulen et al. (1994) to also have a heterozygous mutation in the ERCC3 gene (F99S; 133510.0002). Both men had early onset of severe sunburn and freckle-like skin pigmentation. Other features included short stature, early-onset sensorineural hearing loss, immature sexual development, and late-onset neurologic impairment with hyperreflexia, demyelinating neuropathy, enlarged cerebral ventricles, and retinopathy. Neither patient had skin cancers.
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