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HGNC Approved Gene Symbol: ERCC6
SNOMEDCT: 890434000;
Cytogenetic location: 10q11.23 Genomic coordinates (GRCh38) : 10:49,434,881-49,539,538 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q11.23 | ?De Sanctis-Cacchione syndrome | 278800 | Autosomal recessive | 3 |
| {Lung cancer, susceptibility to} | 211980 | Autosomal dominant; Somatic mutation | 3 | |
| {Macular degeneration, age-related, susceptibility to, 5} | 613761 | 3 | ||
| Cerebrooculofacioskeletal syndrome 1 | 214150 | Autosomal recessive | 3 | |
| Cockayne syndrome, type B | 133540 | Autosomal recessive | 3 | |
| Premature ovarian failure 11 | 616946 | Autosomal dominant | 3 | |
| UV-sensitive syndrome 1 | 600630 | Autosomal recessive | 3 |
The ERCC6 gene is part of the nucleotide excision repair (NER) pathway, a complex system that eliminates a broad spectrum of structural DNA lesions, including ultraviolet (UV)-induced cyclobutane pyrimidine dimers, bulky chemical adducts, and DNA cross-links. ERCC6 belongs to the NER pathway that preferentially repairs lesions on the transcribed strand of active genes; this process occurs more rapidly than repairs on nontranscribed strands that are part of overall genome repair (Troelstra et al., 1992).
Over 43 million years before marmosets diverged from humans, a PiggyBac transposable element, PGBD3, integrated into intron 5 of the ERCC6 gene. As a result, the ERCC6 gene can generate ERCC6 protein, the nonfunctional PGBD3 transposase itself, and an ERCC6-PGBD3 protein derived from alternative splicing of the first 5 exons of ERCC6 to PGBD3 (Bailey et al., 2012).
Troelstra et al. (1990) used the UV-sensitive, nucleotide excision repair-deficient Chinese hamster mutant cell line UV61 to identify and clone a correcting human gene, termed ERCC6. UV61 harbors a deficiency in the repair of UV-induced cyclobutane pyrimidine dimers, but is only moderately UV-sensitive compared to mutant lines in groups 1 to 5. Northern blot analysis identified 2 ERCC6 mRNAs of 5 and 7-7.5 kb.
Troelstra et al. (1992) further characterized the ERCC6 gene. The deduced 1,493-amino acid protein has an N-terminal domain, followed by an acidic stretch, a glycine-rich region, a central helicase domain, and a nuclear localization signal. It also has 2 putative sites for serine phosphorylation. The helicase region contains 7 consecutive domains conserved between DNA and RNA helicases and thus has a presumed DNA unwinding function. Troelstra et al. (1992) showed that the ERCC6 gene corrected the repair defect in cells from patients with Cockayne syndrome B (CSB; 133540), but had no effect on the UV sensitivity of cells from patients with Cockayne syndrome A (216400) or cells from the nucleotide excision repair-defective disorder xeroderma pigmentosum (XP; see, e.g., 278700). Mutation analysis of a patient with CSB indicated that the gene is not essential for cell viability, but is specific for preferential repair of lesions from the transcribed strand of active genes. In light of these observations and in keeping with the nomenclature recommendations of Lehmann et al. (1994), the ERCC6 gene was referred to as CSB.
Troelstra et al. (1993) identified an ERCC6 splice variant that lacked exon 8. This variant introduces a frameshift and was predicted to encode a protein truncated within the helicase domain. Northern blot analysis of HeLa cells and CHO cells expressing human ERCC6 detected expression of a 7-kb transcript and lower expression of a 5-kb transcript. These transcripts differed in the length of their 3-prime untranslated regions (UTRs) only. Use of a 5-prime probe also revealed expression of a 3.5-kb transcript, which was not detected in mouse. In mouse tissues, higher expression of the 7-kb transcript, and weaker expression of the 5-kb transcript, was detected in brain. The smaller transcript was detected in testis, and no Ercc6 expression was detected in mouse thymus or kidney.
By immunohistochemistry and in situ hybridization on rhesus monkey ovarian tissue, Qin et al. (2015) observed that ERCC6 was exclusively expressed in the nuclei of oocytes from primordial, primary, secondary, and antral follicles. Western blot in human ovarian tissue, granulosa cells, heart tissue, and COV434 cells confirmed localization in the ovary but not granulosa cells.
CSB/PGBD3 Protein
Intron 5 of the human CSB gene is host to a PiggyBac transposable element known as PGBD3. By database analysis, Newman et al. (2008) identified a CSB splice variant, which they called CSB-PGBD3, that included the first 5 exons of full-length CSB spliced in-frame to the entire PGBD3 transposase, which contains a 3-prime splice site in-frame with the 5-prime splice site of CSB exon 5. PGBD3 functions as an alternative 3-prime terminal exon and includes a polyadenylation signal. The deduced 1,061-amino acid CSB-PGBD3 protein has a calculated molecular mass of 120 kD and consists of the 465 amino acids of the CSB N terminus spliced to PGBD3. PGBD3 was predicted to be an inactive transposase due to critical mutations within its catalytic domain. Qualitative RT-PCR detected abundant expression of both full-length CSB and CSB-PGBD3. Western blot analysis detected major proteins with apparent molecular masses of about 170 and 140 kD, representing CSB and CSB-PGBD3, respectively, in immortalized WI-38 human lung fibroblasts. CSB-PGBD3 alone was detected in CSB-mutant cells. Newman et al. (2008) also identified a possible additional variant initiating at a putative cryptic promoter in CSB and encoding PGBD3 only.
Bailey et al. (2012) stated that a CSB transcript that is expressed from the internal promoter in CSB exon 5 encodes PGBD3 alone and is an abundant transcript.
Troelstra et al. (1993) determined that the ERCC6 gene contains at least 21 exons and spans up to 90 kb. The first and last exons are noncoding, and intron 1 contains a CpG island. The 5-prime end contains 2 polyadenylation signals.
Newman et al. (2008) identified a PiggyBac transposable element, PGBD3, that resides within ERCC6 intron 5 and contains its own potential polyadenylation signal. They also identified a putative cryptic internal promoter within exon 5 of the ERCC6 gene.
By in situ hybridization, Hoeijmakers et al. (1989) mapped the ERCC6 gene to chromosome 10q11.
By in situ hybridization and Southern blot analysis of mouse/human somatic cell hybrids, Troelstra et al. (1992) localized the ERCC6 gene to 10q11-q21.
Using database analysis, Newman et al. (2008) identified a CSB exon originating from the PiggyBac transposase PGBD3 in chimpanzee and rhesus macaque, and possibly in orangutan and marmoset, but not in more distantly-related primates or other mammals. Marmoset and humans shared a common ancestor approximately 43 million years ago. Human and marmoset PGBD3 encode sequences with 96.5% amino acid identity. The sequence appeared to be under strong purifying selection, including conservation of a mutation within the transposase catalytic domain that compromised its mobility.
Guzder et al. (1996) purified the Rad26 protein to near homogeneity from yeast cells and showed that it is a DNA-dependent ATPase. They discussed the possible role of Rad26 ATPase in the displacement of stalled RNA polymerase II from the site of the DNA lesion and in the subsequent recruitment of a DNA repair component.
Selby and Sancar (1997) tested the effects of purified CSB protein on transcription and found that it enhanced elongation by RNA polymerase II (see 180660). They suggested that a deficiency in transcription elongation may contribute to the Cockayne syndrome phenotype.
Yu et al. (2000) showed that loss of the ERCC6 protein or overexpression of the C-terminal domain of p53 (TP53; 191170) induced fragility of the RNU1 (180680), RNU2 (180690), and RN5S (180420) genes and the ancient PSU1 locus, which consists entirely of pseudogenes. Moreover, they found that p53 interacted with ERCC6 in vivo and in vitro. Yu et al. (2000) proposed that ERCC6 functions as an elongation factor for transcription of structured RNAs, including some mRNAs. Activation of p53 inhibited ERCC6, stalling transcription complexes and locally blocking chromatin condensation.
Lee et al. (2002) provided evidence that Rad2, the S. cerevisiae counterpart of XPG (133530), is involved in promoting efficient RNA polymerase II transcription. Inactivation of Rad26, the S. cerevisiae counterpart of the human CSB gene (ERCC6), also caused a deficiency in transcription, and a synergistic decline in transcription occurred in the absence of both the Rad2 and Rad26 genes. Growth was also retarded in Rad2-deletion and Rad26-deletion single mutant strains, and a very severe growth inhibition was seen in Rad2-deletion/Rad26-deletion double mutants.
Bradsher et al. (2002) provided evidence that CSB is found not only in the nucleoplasm but also in the nucleolus within a complex, which they termed CSBIP/150, that contains RNA polymerase I (see 602000), TFIIH (see 189972), and XPG and promotes efficient rRNA synthesis. CSB was active in in vitro RNA polymerase I transcription and restored rRNA synthesis when transfected in CSB-deficient cells. Mutations in the CSB gene, as well as in the XPB (133510) and XPD (278730) genes, all of which confer Cockayne syndrome, disturbed the RNA polymerase I/TFIIH interaction within the CSBIP/150 complex.
Licht et al. (2003) reviewed the cellular and biochemical functions of the CSB gene. They pointed out that the CSB protein is at the interface of transcription and DNA repair and is involved in transcription-coupled and global genome-DNA repair, as well as in general transcription. They found that more than 180 cases of Cockayne syndrome have been reported from different parts of the world, with no apparent overrepresentation in any specific population. Of patients with Cockayne syndrome, approximately 80% had mutations in the CSB gene, and the others carried mutated CSA alleles. They provided a table of more than a dozen proteins that interact with or are in complex with CSB. Licht et al. (2003) provided a tentative model for CSB function in transcription and in transcription-coupled repair.
By immunoprecipitation analysis of HeLa cells, Thorslund et al. (2005) found that endogenous CSB interacted directly with PARP1 (173870), a nuclear DNA damage surveillance protein that modifies substrate proteins by poly(ADP-ribosyl)ation in response to oxidative DNA damage. PARP1 is also subject to auto-poly(ADP-ribosyl)ation. Recombinant PARP1 bound to the CSB N-terminal domain prior to the acidic region, resulting in CSB poly(ADP-ribosyl)ation and reducing its DNA-dependent ATPase activity. CSB interacted with both unmodified PARP1 and poly(ADP-ribosyl)ated PARP1. In unstressed HeLa cells, CSB colocalized with PARP1 in nucleoli, but following H2O2-induced oxidative damage, CSB colocalized with PARP1 in the nucleoplasm. CSB-deficient and CSB-null cells were sensitive to PARP inhibition, likely due to loss of transcription-coupled repair, which depends upon CSB ATPase activity.
Using expression arrays and comparative expression analysis, Newman et al. (2006) found that expression of wildtype CSB in CS patient fibroblasts induced significant changes in gene expression, even in the absence of external stress. Many of the genes regulated by CSB were also affected by inhibitors of histone deacetylase (see 601241) and DNA methylation, as well as by defects in poly(ADP-ribose) polymerase (see 173870) function and RNA polymerase II elongation. Newman et al. (2006) concluded that CSB has a general role in chromatin maintenance and remodeling.
By comparing wildtype cells to CSB patient cell lines or to CSB-knockdown wildtype cells, Proietti-De-Santis et al. (2006) found that loss of functional CSB inhibited recovery of RNA synthesis following UV exposure. In wildtype cells, CSB, RNA pol II (see 180660), and TFIIB (189963) were detected at promoter regions of housekeeping genes, but CSB mutation or silencing of CSB prevented recruitment of RNA pol II to promoters and caused defective histone H4 acetylation. CSB associated mainly with unphosphorylated RNA pol II; CSB mutant cells also showed a defect in RNA pol II phosphorylation and decreased basal transcription. Proietti-De-Santis et al. (2006) concluded that CSB is involved in the first phases of RNA transcription.
Ribosomal DNA (rDNA) transcription requires binding of TTF1 (600777) to the promoter-proximal terminator T(0) located adjacent to the transcription start site. Binding of TTF1 mediates ATP-dependent nucleosome remodeling, which correlates with efficient transcription initiation. Using mouse and human cell lines, Yuan et al. (2007) showed that CSB was recruited to active rDNA repeats by TTF1 bound to T(0). CSB was associated with RNA polymerase I and was present both at the promoter and pre-rRNA coding regions. Depletion of CSB by small interfering RNA impaired formation of polymerase I preinitiation complexes and inhibited rDNA transcription. Moreover, CSB interacted with histone methyltransferase G9A (BAT8; 604599), and functional G9A was required for rDNA transcription. Yuan et al. (2007) concluded that cooperation between CSB and G9A is required for efficient pre-rRNA synthesis.
Using dot blot analysis and ELISA, Wong et al. (2007) showed that human CSB interacted with APE1 (APEX1; 107748), the major apurinic/apyrimidinic (AP) endonuclease. CSB stimulated AP site incision activity of APE1 on normal (i.e., fully paired) and bubble AP-DNA substrates, with the latter being more pronounced. The activation was ATP independent and specific for human CSB and full-length APE1. Immunoprecipitation analysis showed that CSB and APE1 were present in a common protein complex in human cell extracts, and addition of CSB to CSB-deficient whole cell extracts increased total AP site incision capacity. Moreover, human fibroblasts deficient in CSB were hypersensitive to agents that introduce base excision repair DNA substrates/intermediates.
Independently, Zhang et al. (2012) and Schwertman et al. (2012) showed that UVSSA (614632) stabilized ERCC6 by delivering ubiquitin-specific protease-7 (USP7; 602519) to the NER complex. They concluded that UVSSA-USP7-mediated stabilization of ERCC6 is a critical regulatory mechanism of transcription-coupled NER.
CSB/PGBD3 Protein
Using expression array analysis with transfected cells derived from the patient of Horibata et al. (2004) with a nonsense mutation in CSB codon 77 (609413.0009), Bailey et al. (2012) found that CSB and CSB-PGBD3 could regulate gene expression independently, synergistically, or antagonistically. In addition, CSB-PGBD3 interacted with a subset of conserved MER85 elements, which had been derived from PGBD3 when it was an active transposon but lack the central transposase open reading frame. CSB-PGBD3 had significant activity on its own or synergistically with CSB in repair of UV and oxidative DNA damage.
Cockayne Syndrome B
In 16 patients with Cockayne syndrome B (CSB; 133540), Mallery et al. (1998) identified 18 inactivating mutations in the ERCC6 gene (see, e.g., 609413.0001-609413.0003). In 9 patients, the mutations resulted in truncated products in both alleles, whereas in the other 7 patients, at least 1 allele contained a single amino acid change. The latter mutations were confined to the C-terminal two-thirds of the protein and were shown to be inactivating by their failure to restore UV-irradiation resistance to hamster UV61 cells, which are known to be defective in the CSB gene. Neither the site nor the nature of the mutation correlated with the severity of the clinical features; severe truncations were found in different patients with either classic or early-onset forms of the disease.
Cultured cells from sun-sensitive Cockayne syndrome patients are hypersensitive to ultraviolet light and are unable to restore RNA synthesis rates to normal levels following UV irradiation. This defect has been attributed to a specific deficiency in CS cells in the ability to carry out preferential repair of damage in actively transcribed regions of DNA. Colella et al. (1999) reported a cellular and molecular analysis of 3 Italian CS patients who were of particular interest because none of them was sun-sensitive, despite showing most of the features of the severe form of CS, including the characteristic cellular sensitivity to UV irradiation. Two related patients were homozygous for a nonsense mutation in the ERCC6 gene (609413.0004). A third patient was a compound heterozygote for 2 mutations. All 3 mutations resulted in severely truncated proteins, confirming that the CSB gene is not essential for viability and cell proliferation, an important issue to be considered in any speculation on the proposed function of the CSB protein in transcription. The finding supported the notion that other factors, beside the site of the mutation, influence the type and severity of the CS clinical features.
In 3 affected members of a large Druze kindred with severe Cockayne syndrome B, Falik-Zaccai et al. (2008) identified a homozygous mutation in the ERCC6 gene (609413.0011). The carrier frequency was 1:15 among healthy Druze individuals from the same village.
UV-Sensitive Syndrome 1
UV-sensitive syndrome-1 (UVSS1; 600630) is a rare autosomal recessive disorder characterized by photosensitivity and mild freckling but without the neurologic abnormalities or skin tumors of known photosensitive disorders such as xeroderma pigmentosum or Cockayne syndrome. In a cell line from a patient with UV-sensitive syndrome, Horibata et al. (2004) found that microcell-mediated transfer of chromosome 10 corrected the UV hypersensitivity, causing these cells to acquire UV resistance. Because the gene responsible for Cockayne syndrome group B is located on chromosome 10, they sequenced the gene in this cell line and identified a homozygous null mutation (609413.0009). Another cell line from an unrelated patient with UV-sensitive syndrome had no mutation in the ERCC6 cDNA and a normal amount of the protein was detected.
Cerebrooculofacioskeletal Syndrome 1
Cerebrooculofacioskeletal syndrome (see COFS1, 214150) is an autosomal recessive progressive brain and eye disorder leading to cerebral atrophy, hypoplasia of the corpus callosum, hypotonia, severe mental retardation, cataracts, microcornea, optic atrophy, progressive joint contractures, and postnatal growth deficiency. Meira et al. (2000) demonstrated an identical mutation in the ERCC6 gene (609413.0007) in 2 probands from the Manitoba aboriginal population group within which COFS syndrome was originally delineated by Pena and Shokeir (1974). They found that the 2 probands showed cellular phenotypes indistinguishable from those of Cockayne syndrome cells.
In 3 unrelated patients with COFS syndrome, Laugel et al. (2008) identified biallelic mutations in the ERCC6 gene (see, e.g., 609413.0012-609413.0014). All patients showed classic clinical features of the disorder and cultured fibroblasts showed defective DNA repair.
Age-Related Macular Degeneration 5
In a cohort of 460 advanced cases of age-related macular degeneration (ARMD5; 613761) and 269 age-matched controls and 57 archived ARMD cases and 18 age-matched non-ARMD controls, Tuo et al. (2006) found that a -6530C-G SNP (609413.0010; rs3793784) in the ERCC6 gene was associated with ARMD susceptibility, both independently and through interaction with an intronic SNP in the CFH gene (rs380390; 134370.0008) previously reported to be highly associated with ARMD.
Premature Ovarian Failure 11
In a Han Chinese family in which 4 women over 2 generations experienced secondary amenorrhea (POF11; 616946), Qin et al. (2015) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the ERCC6 gene (G746D; 609413.0016) that segregated with disease in the family and was not found in the 1000 Genomes Project or dbSNP (build 134) databases. Analysis of ERCC6 in 432 sporadic Chinese POF patients revealed 2 women with heterozygous mutations in ERCC6: a nonsense mutation (E215X; 609413.0017) and a missense mutation (V1056I), neither of which was found in 400 Chinese female controls. Qin et al. (2015) noted that premature ovarian failure had not been reported in any of the families of patients with Cockayne syndrome (CSB; 133450), in which one would expect there to be heterozygous women. The authors proposed that the novel sporadic mutations may act in a dominant-negative fashion.
Trapp et al. (2007) stated that Ogg1 (601982) deficiency in mice leads to elevated basal levels of 7,8-dihydro-8-oxo-2-prime-deoxyguanosine (8-oxoG) and increased spontaneous mutation frequency, although repair of 8-oxoG is not completely abolished. To elucidate the role of CSB in preventing mutations caused by oxidative DNA base damage, Trapp et al. (2007) generated mice deficient in Ogg1 (Ogg1 -/-), Csb (Csb m/m, which have a truncating mutation), or both Csb and Ogg1 (Csb m/m Ogg1 -/-) that carried a nontranscribed bacterial lacI gene for mutation analysis. The overall spontaneous mutation frequency in livers of Csb m/m Ogg1 -/- mice were elevated compared with heterozygous control mice and Ogg1 -/- mice. The additional mutations caused by Csb m/m in the Ogg1 -/- background were mostly GC-to-TA transversions and small deletions. For all mouse strains, the background levels of oxidative purine modification in livers correlated linearly with the number of GC-to-TA transversions. Trapp et al. (2007) concluded that CSB inhibits spontaneous oxidative DNA base damage in nontranscribed genes.
Gorgels et al. (2007) found that mice carrying a truncating mutation in Ercc6 (Csb m/m) were hypersensitive to UV light and developed epithelial hyperplasia and squamous cell carcinomas in the cornea, neither of which had been reported in CS patients. Csb m/m mice were predisposed to spontaneous retinal degeneration with age and had increased apoptotic photoreceptor cells compared to wildtype following exposure to ionizing radiation. Quantitative PCR revealed moderate to substantial increase in the expression of oxidative stress markers, suggesting that the premature aging features of CS may be due to oxidative DNA damage.
The article by Fousteri et al. (2006) regarding the function of CSB and CSA in TCR complex formation was retracted because an investigation at the Leiden University Medical Center concluded that 'unacceptable data manipulation by the first author Maria Fousteri led to breaches of scientific integrity, making these results unreliable.'
In a Turkish patient with Cockayne syndrome B (CSB; 133540), Mallery et al. (1998) identified a homozygous 1630G-A transition in the ERCC6 gene, resulting in a trp517-to-ter (W517X) substitution. The patient was born of consanguineous parents.
In a Turkish patient with Cockayne syndrome B (CSB; 133540) and consanguineous parents, Mallery et al. (1998) identified a homozygous 2282C-T transition in the ERCC6 gene, resulting in an arg735-to-ter (R735X) substitution. This same truncating mutation was found in compound heterozygous state with an arg453-to-ter (R453X; 609413.0004) mutation in another patient studied by Mallery et al. (1998).
Colella et al. (2000) demonstrated homozygosity for the R735X mutation in the ERCC6 gene in 2 sibs with de Sanctis-Cacchione syndrome (278800), a form of xeroderma pigmentosum associated with severe neurologic involvement. The authors concluded that there is no simple correlation between molecular defects in Cockayne syndrome B and clinical features, and that other genetic and/or environmental factors may determine the pathologic phenotype.
In a rare example of a black patient with Cockayne syndrome (CSB; 133540), Mallery et al. (1998) identified compound heterozygosity for 2 mutations in the ERCC6 gene: a 1-bp deletion (1597delG) in the center of a 12-bp inverted repeat, resulting in a stop codon at residue 506, and a 3363G-C transversion, resulting in a pro1095-to-arg (P1095R; 609413.0008) substitution. However, based on a review of the P1095R variant in the ExAC database (December 7, 2016) by Hamosh (2016), that missense mutation has been reclassified as a variant of unknown significance.
Colella et al. (1999) found that 2 first-cousin Italian patients with Cockayne syndrome (CSB; 133540) were homozygous for a 1436C-T transition in the ERCC6 gene, resulting in an arg453-to-ter (R453X) substitution. Both patients had a severe form of Cockayne syndrome without clinical photosensitivity.
In an Italian patient with a severe form of Cockayne syndrome (CSB; 133540) but without clinical photosensitivity, Colella et al. (1999) found compound heterozygosity for 2 mutations in the ERCC6 gene: a 1-bp insertion (1051insA) in codon 325, leading to frameshift and creation of a premature termination at codon 368; and a 4-bp insertion (1053insTGTC) in codon 659, causing a frameshift and creation of a premature termination at codon 682 (609413.0006). The protein in these 2 cases had 367 and 681 amino acids, respectively. The normal protein has 1,493 amino acids.
For discussion of the 4-bp insertion (1053insTGTC) in the ERCC6 gene that was found in compound heterozygosity in a patient with a severe form of Cockayne syndrome (CSB; 133540) but without photosensitivity by Colella et al. (1999), see 609413.0005.
In 2 patients related to the Manitoba aboriginal population group in which cerebrooculofacioskeletal syndrome (COFS1; 214150) was originally reported, Meira et al. (2000) identified a homozygous 2-bp deletion (3794delAA) in the ERCC6 gene. The deletion is predicted to result in a truncated polypeptide missing the C-terminal 254 amino acids. The identical mutation was observed in 1 ERCC6 allele in each parent of 1 patient.
This variant, formerly designated COCKAYNE SYNDROME B, has been reclassified based on a review of the ExAC database by Hamosh (2016).
In a rare example of a black patient with Cockayne syndrome (CSB; 133540), Mallery et al. (1998) identified compound heterozygosity for 2 mutations in the ERCC6 gene: a 1-bp deletion (1597delG; 609413.0003) in the center of a 12-bp inverted repeat, and a 3363G-C transversion, resulting in a pro1095-to-arg (P1095R) substitution.
Hamosh (2016) noted that the P1095R variant in the ExAC database (December 7, 2016) has a high allele frequency (0.04192) in the African population and has been found in homozygosity in 10 Africans, suggesting that the variant is not pathogenic.
In cells from a patient with UV-sensitive syndrome-1 (UVSS1; 600630) previously reported by Fujiwara et al. (1981), Horibata et al. (2004) identified a homozygous C-to-T transition in the ERCC6 gene, resulting in an arg77-to-ter (R77X) substitution. The results indicated that only truncated ERCC6 polypeptides containing the 76-amino acid N terminus of the ERCC6 protein were produced, if any, in the cells. The parents, who were first cousins and did not have abnormal photosensitivity, were heterozygous for the mutation. The patient exhibited a number of freckles, hypopigmented spots, telangiectases, and slightly dried skin in sun-exposed areas, but no growth retardation or neurologic abnormalities, at age 8 years. The patient was 33 years of age at the time of report. He had been healthy except for abnormal photosensitivity. He was 183 cm tall and weighed 64 kg. He had a slightly dark basal skin color and numerous small spots of pigmentation on his face, the extensor surface of his forearms, and the back of his hands. He had had no skin cancers and no neurologic abnormalities.
In a Japanese patient with UVSS assigned to Cockayne syndrome B based on complementation studies (Miyauchi-Hashimoto et al., 1998), Nakazawa et al. (2012) identified a homozygous R77X mutation in the ERCC6 gene. The phenotype was consistent with UVSS1.
Bailey et al. (2012) stated that cells derived from the patient of Horibata et al. (2004) carrying this mutation expressed neither full-length CSB nor CSB-PGBD3.
In a cohort of 460 ARMD cases and 269 age-matched controls and 57 archived ARMD cases and 18 age-matched non-ARMD controls, Tuo et al. (2006) found that a -6530C-G SNP (rs3793784) in the 5-prime flanking region of the ERCC6 gene was associated with ARMD5 susceptibility (613761), both independently and through interaction with an intronic G-C SNP in the CFH gene (rs380390; 134370.0008) previously reported to be highly associated with ARMD. A disease odds ratio of 23 was conferred by homozygosity for risk alleles at both ERCC6 and CFH (G allele and C allele, respectively) compared to homozygosity for nonrisk alleles. Tuo et al. (2006) suggested that the strong ARMD predisposition conferred by the ERCC6 and CFH SNPs may result from biologic epistasis. In functional studies on the -6530C-G SNP, Tuo et al. (2006) found that the SNP conferred a distinct change in regulation of gene expression in vitro and in vivo, with enhanced expression associated with the G allele.
Lin et al. (2008) found that the -6530C allele has about 2-fold decreased transcriptional activity as well as decreased binding affinity of nuclear proteins compared to the G allele. In a case-control study of 1,000 Chinese patients with various types of lung cancer (see 211980) and 1,000 Chinese controls, those with the CC genotype had a 1.76-fold increased risk of disease compared to those with the CG or GG genotypes (p = 10(-9)). The C allele also interacted with smoking to intensify lung cancer risk, yielding an odds ratio of 9.0 for developing cancer among heavy smokers.
In affected members of a large Druze kindred with severe Cockayne syndrome B (CSB; 133540), Falik-Zaccai et al. (2008) identified a homozygous 1-bp insertion (1034insT) in exon 5 of the ERCC6 gene resulting in a frameshift and premature termination. All patients were severely affected and died by age 5 years. The mutation was identified in 7 of 106 healthy Druze individuals from the same village, indicating a high carrier frequency of 1:15.
In a Scottish male infant with cerebrooculofacioskeletal syndrome (COFS1; 214150), Laugel et al. (2008) identified a homozygous 2047C-T transition in the ERCC6 gene, resulting in an arg683-to-ter (R683X) substitution. He had classic features of the syndrome, including microcephaly, overhanging upper lip, a prominent nasal root, congenital cataracts, arthrogryposis, and rocker bottom feet. He showed severe feeding and respiratory difficulties, and died from respiratory failure at age 10 months. DNA repair studies on cultured fibroblasts showed increased sensitivity to UV irradiation and a severe decrease in recovery of RNA synthesis after UV irradiation.
In a girl with cerebrooculofacioskeletal syndrome (COFS1; 214150), Laugel et al. (2008) identified compound heterozygosity for 2 mutations in the ERCC6 gene: a 2960T-C transition, resulting in a leu987-to-pro (L987P) substitution in a conserved region, and a 2254A-G transition in exon 11 (609413.0014), resulting in the creation of a novel donor splice site and a deletion of 11 residues of exon 11. She had arthrogryposis, mild talipes equinovarus, flexed wrists, and clenched fingers. Dysmorphic features included microphthalmia, congenital cataracts, prominent metopic suture, and an overhanging upper lip. Other features included severe feeding difficulties and delayed developmental milestones. DNA repair studies on cultured fibroblasts showed increased sensitivity to UV irradiation and a severe decrease in recovery of RNA synthesis after UV irradiation.
For discussion of the 2254A-G transition in the ERCC6 gene that was found in compound heterozygosity in a patient with cerebrooculofacioskeletal syndrome-1 (COFS1; 214150) by Laugel et al. (2008), see 609413.0013.
In 3 of 6 affected members of a large consanguineous Finnish family with cerebrooculofacioskeletal syndrome (COFS1; 214150), Jaakkola et al. (2010) identified a homozygous 3862C-T transition in the ERCC6 gene, resulting in an arg1288-to-ter (R1288X) substitution. Two of the patients had originally been reported by Linna et al. (1982); the R1288X mutation was found in paraffin-embedded tissue from 1 of these patients. Fibroblast studies showed that the mutation caused a severe reduction of the encoded protein to 20% of controls. Genealogic analysis revealed that common ancestors for all the patients lived in the 18th century in a small village in northern Finland, consistent with a founder effect.
In a Han Chinese family in which 4 women over 2 generations experienced secondary amenorrhea (POF11; 616946), Qin et al. (2015) identified heterozygosity for a c.2237G-A transition (c.2237G-A, ENST00000515869) in the ERCC6 gene, resulting in a gly746-to-asp (G746D) substitution. The mutation segregated with disease in the family and was not found in the 1000 Genomes Project or dbSNP (build 134) databases. In transiently transfected U2OS and HeLa cells that were exposed to laser microirradiation or oxidative damage, the mutant response to DNA damage was much weaker than wildtype, with a significantly lower percentage of mutant cells recruited to sites of DNA damage (22% vs 73%). Clonogenic survival assay also demonstrated that the survival percentage of wildtype cells was significantly higher than that of cells expressing G746D.
In a Chinese woman who experienced secondary amenorrhea at age 24 years (POF11; 616946), Qin et al. (2015) identified heterozygosity for a c.643G-T transversion (c.643G-T, ENST00000515869) in exon 4 of the ERCC6 gene, resulting in a glu215-to-ter (E215X) substitution at a highly conserved residue. The mutation was not found in 400 Chinese female controls. In transiently transfected U2OS and HeLa cells that were exposed to laser microirradiation or oxidative damage, the E215X mutant showed no accumulation at laser-damaged sites. The mutant bound initially to peroxide-treated chromatin, but separated from it rapidly and showed no aggregation at 15 minutes, which was the peak point of recruitment for wildtype ERCC6, suggesting that E215X may not participate in DNA damage repair. In addition, the truncated mutant failed to associate with RNA polymerase II (see 180660) after ultraviolet or peroxide damage. Clonogenic survival assay also demonstrated that the survival percent of wildtype cells was significantly higher than that of cells expressing E215X.
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