* 611153

XPA, DNA DAMAGE RECOGNITION AND REPAIR FACTOR; XPA


Alternative titles; symbols

XPA GENE
XPA COMPLEMENTING GENE; XPAC


HGNC Approved Gene Symbol: XPA

Cytogenetic location: 9q22.33     Genomic coordinates (GRCh38): 9:97,654,398-97,697,340 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
9q22.33 Xeroderma pigmentosum, group A 278700 AR 3

TEXT

Description

The XPA gene encodes a protein involved in DNA excision repair (Tanaka et al., 1990).


Cloning and Expression

Tanaka et al. (1989, 1990) cloned a mouse gene that restored UV light-resistance in 2 cell lines from patients with xeroderma pigmentosum complementation group A (XPA; 278700). No correction was observed in relation to other XP groups. Tanaka et al. (1989) concluded that they had succeeded in cloning the mouse homolog of the gene that is mutant in XPA.

Tanaka et al. (1990) cloned a cDNA corresponding to the human XPA gene. The deduced 273-amino acid protein has a calculated molecular mass of 31 kD. The human protein is 95% similar to the mouse protein and contains several alpha-helices and a zinc-finger motif, consistent with a DNA-binding protein. Two mRNAs, 1.3-1.4 kb and 1.0-1.1 kb, were detected in normal human cells. Sequence analysis identified a truncated XPA protein that could be translated from an ATG present at position 176, which retained sufficient function to partially restore the DNA repair defect in XPA cells. A 1.0-1.1-kb mouse Xpa mRNA was also identified. Expression of XPA cDNA conferred UV resistance to several cells derived from patients with xeroderma pigmentosum complementation group A, but not with other XP complementation groups.

Shimamoto et al. (1991) compared the homologous Xpa genes in chicken, Xenopus laevis, and Drosophila melanogaster with the human gene. A high level of conservation was found in the COOH-terminal domain where the frequency of identical amino acids was about 50% with preservation of the zinc finger motif, suggesting that this portion of the gene plays an important role in the function of the protein.

In the yeast Saccharomyces cerevisiae, any one of 5 genes, RAD1, RAD2, RAD3, RAD4, and RAD10, causes a total defect in the incision step of excision repair of DNA damaged by ultraviolet light and an extreme sensitivity to ultraviolet light. Bankmann et al. (1992) reported the characterization of the yeast RAD14 gene and found that it encodes a highly hydrophilic 247-residue protein containing zinc finger motifs with high similarity to the protein encoded by the human XPA gene. Studies with a RAD14 deletion mutation indicated the absolute requirement of the gene in the DNA incision process.


Gene Structure

Miyamoto et al. (1992) determined that the XPA gene contains 6 exons. Studies using site-directed mutagenesis showed that the nuclear localization signal of the XPA gene is located in the region encoded by exon 1, whereas exons 2 through 6 are essential for the DNA repair function. All 4 cysteines forming a zinc finger structure and also the glutamic acid cluster in the region encoded by exon 2 were found to be important for DNA repair function.


Mapping

Using mouse-human hybrid cell lines, Kaur and Athwal (1989) achieved complementation of the repair defect in xeroderma pigmentosum group A cells by the transfer of human chromosome 9. Henning et al. (1990) showed that microcell-mediated transfer of a single rearranged human chromosome from a human-mouse somatic cell hybrid resulted in specific complementation of defective repair and UV sensitivity in XPA cells. Cytogenetic analysis and Southern blot analysis localized the XPA gene to chromosome 9q22.2-q34.3.

Using microcell fusion studies, Ishizaki et al. (1990) demonstrated that 7 of 11 recipient XP clones became UV-resistant after transfer of chromosome 9. Southern hybridization analysis confirmed that at least part of a normal human chromosome 9 had been transferred into recipient clones.

Tanaka et al. (1990) localized the human and mouse XPAC genes to 9q34.1 and 4C2, respectively, by in situ hybridization.

Farndon et al. (1994) stated that the XPAC gene, like the basal cell nevus syndrome gene (NBCCS; 109400), the gene for self-healing squamous epithelioma (MSSE; 132800), and the group C Fanconi anemia gene (FACC; 227645), all map to 9q22.3-q31. Lench et al. (1996) created an EST- and STS-based YAC contig map of human 9q22.3 and showed that it contains the following genes in this order, from centromere to telomere: TMOD (190930), XPA, ALDOB (612724), BAAT (602938). The 4 genes are located in a syntenic region of mouse chromosome 4 and are arranged in the same order as their human counterparts on 9q.


Gene Function

Li et al. (1994) demonstrated that the XPA protein associates in a specific manner with ERCC1 (126380). They suggested that one possible function of XPA is the loading and perhaps the orientation of an incision complex, containing ERCC1 and other factors, to the site of DNA damage. Park and Sancar (1994) concluded from their studies that XPA, ERCC1, and ERCC4 (133520) proteins form a ternary complex that participates in both damage recognition and incision activities. Using site-specific mutagenesis, Li et al. (1995) found that the association between XPA and ERCC1 is a required step in the nucleotide excision repair pathway and that the probable role of the interaction is to recruit the ERCC1 incision complex to the damaged site.

Excision repair of bulky DNA adducts, such as those formed by the cancer chemotherapy agent cisplatin, appears to be mediated by an aggregate of genes, with the XPAC and ERCC1 proteins being involved in DNA damage recognition and excision. Dabholkar et al. (1994) assessed mRNA levels of ERCC1 and XPAC in malignant ovarian cancer tissues from 28 patients that were harvested before the administration of platinum-based chemotherapy. They found that cancer tissues from patients whose tumors were clinically resistant to therapy showed greater levels of total ERCC1 mRNA, full-length transcript of ERCC1 mRNA, and XPAC mRNA, as compared with tumor tissues from those individuals clinically sensitive to therapy. The number of patients in the 2 groups were 13 and 15, respectively.

Volker et al. (2001) described the assembly of the NER complex in normal and repair-deficient (xeroderma pigmentosum) human cells by employing a novel technique of local ultraviolet irradiation combined with fluorescent antibody labeling. The damage-recognition complex XPC (613208)-HR23B (RAD23B; 600062) appeared to be essential for the recruitment of all subsequent NER factors in the preincision complex, including transcription repair factor TFIIH (see 189972). Volker et al. (2001) found that XPA associates relatively late, is required for anchoring of ERCC1-XPF, and may be essential for activation of the endonuclease activity of XPG (133530). These findings identified XPC as the earliest known NER factor in the reaction mechanism, gave insight into the order of subsequent NER components, provided evidence for a dual role of XPA, and supported a concept of sequential assembly of repair proteins at the site of damage rather than a preassembled repairosome.

By yeast 2-hybrid analysis, Nitta et al. (2000) identified XAB1 (611479) as an XPA-binding protein. Mutation analysis showed that XAB1 specifically bound residues 30 to 34 of XPA.

Lembo et al. (2003) found that coexpression of XPA, MBD2 (603547), and XAB1 in 293T cells resulted in their coimmunoprecipitation, and the results suggested that XAB1 functions as a bridge between MBD2 and XPA.


Molecular Genetics

In multiple cell lines derived from Japanese patients with XP group A, Tanaka et al. (1990) identified a homozygous mutation in the XPA gene (611153.0001).

Cleaver et al. (1995) reported novel deletion and insertion mutations in a family with 2 daughters previously classified as homozygous for defects in the XPA gene (Davis et al., 1994). One mutation was a 20-bp deletion in exon 4; the other was a 1-bp adenine insertion in exon 5 in a region normally consisting of 6 adenines. Owing to the presence of multiple adenines in affected regions of both alleles, the precise bases that were lost or inserted to generate the observed alterations were ambiguous. The 20-nucleotide deletion was found to be from the maternal allele.

In patients with XPA, Satokata et al. (1992, 1992) identified homozygous or compound heterozygous mutations in the XPA gene (611153.0002-611153.0006).

Cleaver et al. (1999) reviewed mutations identified in the XPA gene and their population frequencies.


Genotype/Phenotype Correlations

States et al. (1998) performed a mutation analysis on XPA cell lines from 19 American and European patients. Most mutations were deletions and splice site mutations, observed previously in other XPA patients in exon 3, intron 3, or exon 4, that resulted in frameshifts within the DNA-binding region. One new mutation was a point mutation within intron 3 causing a new splice acceptor site that may compete with the original splice acceptor site. Mutations in the DNA-binding region of XPA were from patients with the more severe disease often associated with neurologic complications, whereas mutations in the C terminus of the protein, which interacts with the TFIIH transcription factor, were from patients with milder skin disease only. The rarity of naturally occurring missense mutations in the DNA-binding region of XPA suggests that amino acid changes may be sufficiently tolerated such that patients could have mild symptoms and escape detection.


Nomenclature

Lehmann et al. (1994) proposed the following nomenclature scheme for human DNA repair genes: (1) For xeroderma pigmentosum genes, the final C from the XPAC, XPBC, etc., genes should be omitted. The final C should be retained in excision repair cross-complementing (ERCC) genes; (2) where an ERCC gene has been found to be unequivocally identical to a xeroderma pigmentosum, Cockayne syndrome, or trichothiodystrophy (TTD; 601675) gene, the name should eventually be replaced by the corresponding XP, CS, or TTD gene. Thus, ERCC2, ERCC3, and ERCC6 would become the XPD, XPB, and CSB genes, respectively.


Animal Model

Nakane et al. (1995) established Xpa-deficient mice by gene targeting of mouse embryonic stem cells. The Xpa-deficient mice showed neither obvious physical abnormalities nor pathologic alterations, but were defective in nucleotide-excision repair and highly susceptible to ultraviolet-B- and 9,10-dimethyl-1,2-benz[a]anthracene-induced skin carcinogenesis. The findings provided in vivo evidence that the Xpa protein protects mice from carcinogenesis initiated by ultraviolet or chemical carcinogen. Comparable findings were independently reported by de Vries et al. (1995).

Mouse models of XPA have been established by gene targeting and found not to develop clearly detectable neurologic abnormalities, although they do show susceptibility to UV- and chemical carcinogen-induced skin cancer. Similarly, mice who are rendered deficient in the CSB gene (609413), which is deficient in group B Cockayne syndrome (133540), show only a mild neurologic phenotype. Murai et al. (2001) produced mice lacking both the Xpa and the Csb genes and found growth retardation and abnormal behavior closely resembling symptoms observed in human XPA and/or CSB patients at an early postnatal stage. The cerebellum was hypoplastic and showed impaired foliation and stunted Purkinje cell dendrites. The findings suggested that Xpa and Csb have additive roles in the mouse nervous system and support a crucial role for these 2 genes in normal brain development.

De Boer et al. (2002) found that mice with an ERCC2 mutation (R722W; 126340.0014) had many symptoms of premature aging, including osteoporosis and kyphosis, osteosclerosis, early graying, cachexia, infertility, and reduced life span. Trichothiodystrophy (TTD; 601675) 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.


History

Early Mapping Studies

Using hamster-human hybrid cells with various chromosomal constitution, Keijzer et al. (1984) excluded linkage of XP group A to the X chromosome, which had been thought to be involved (Stefanini et al., 1982), and found linkage to chromosome 1q. Keijzer et al. (1987) fused human, Chinese hamster or Chinese hamster/human hybrid cytoplasts with UV-irradiated XPA cells. Unscheduled DNA synthesis in the XP nucleus showed correction of the defect immediately after fusion of human cytoplasts, whereas the Chinese hamster cytoplasts did not show this rapid increase in excision repair. The results obtained after fusion of cytoplasts isolated from a panel of 26 Chinese hamster-human hybrids showed that chromosome 1q42-qter contained genetic information necessary for the rapid correction of the XP defect. However, correction was also observed with cytoplasts from a hybrid cell made between a Chinese hamster cell and an XP cell containing human chromosome 1, suggesting that the correcting factor consisted of both human and Chinese hamster components and that the gene mapped to chromosome 1 may not be the one that is mutated in XP of the A group. In fact, the mapping to chromosome 1 was never confirmed (Cleaver, 1993) and the gene was subsequently mapped to chromosome 9. Kaur et al. (1992) observed partial complementation in XP group A cells by a gene that mapped to human chromosome 8.


ALLELIC VARIANTS ( 7 Selected Examples):

.0001 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, IVS3AS, G-C
  
RCV000246304...

In 19 of 20 Japanese patients with xeroderma pigmentosum complementation group A (278700), Tanaka et al. (1990) identified a G-to-C transversion at the 3-prime splice acceptor site of intron 3 of the XPA gene. Satokata et al. (1990) found that the G-to-C transversion abolished the canonical 3-prime splice site and created 2 abnormally spliced mRNA forms. The larger form was identical with normal mRNA except for a dinucleotide deletion at the 5-prime end of exon 4, which resulted in a frameshift with premature termination of translation in exon 4. The smaller form had a deletion of the entire exon 3 and the dinucleotide at the 5-prime end of exon 4. A single base substitution creates a new cleavage site for the restriction endonuclease AlwNI.

Using the AlwNI RFLP, Satokata et al. (1990) found that 16 of 21 unrelated Japanese patients with XP were homozygous and 4 were heterozygous for this mutation. However, 11 Caucasians and 2 blacks with group A XP did not have this mutant allele. Kore-eda et al. (1992) demonstrated the usefulness of the polymerase chain reaction (PCR) followed by search for the AlwNI RFLP in the diagnosis of XPA.

Cleaver et al. (1995) stated that homozygosity for the G-to-C transversion at the 3-prime acceptor site of intron III/exon IV of the XPA gene represents 80 to 90% of Japanese patients with XPA.

Maeda et al. (1995) reported that patients who were homozygous for the common splice site mutation in intron 3 could walk unaided until 7-16 years of age.


.0002 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, CYS108PHE
  
RCV000001048

In a cell line derived from a patient with XPA (278700), Satokata et al. (1992) found compound heterozygosity for 2 mutations in the XPA gene: a 323G-T transversion resulting in a cys108-to-phe (C108F) substitution that disrupted a putative zinc finger domain, and a 5-bp deletion (611153.0003).


.0003 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, 5-BP DEL
  
RCV000001049...

In a cell line derived from a patient with XPA (278700), Satokata et al. (1992) found compound heterozygosity for 2 mutations in the XPA gene: a 5-bp deletion causing a frameshift and premature termination, and C108F (611153.0002).


.0004 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, ARG228TER
  
RCV000001050...

Satokata et al. (1992) described a C-to-T transition in exon 6 of the XPA gene, resulting in an arg228-to-ter (R228X) substitution, as a cause of XPA (278700). The mutation created a new cleavage site for the restriction endonuclease HphI. Of 21 unrelated XPA patients examined, 1 was homozygous for this mutation and 3 were compound heterozygotes for this mutation and a splice site mutation in intron 3 (611153.0001). The homozygous patient was atypical with mild skin symptoms and minimal neurologic abnormalities.

Xeroderma pigmentosum patients in Tunisia who belong to the genetic complementation group A have milder skin symptoms than do Japanese XPA patients. Nishigori et al. (1993) found that 6 of 7 Tunisian XPA patients had the R228X mutation.

Maeda et al. (1995) reported that a patient who was homozygous for the R228X mutation could walk unaided without any difficulty until the age of 21 years.


.0005 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, ARG207TER
  
RCV000001051...

In a Palestinian patient with severe XPA (278700), Satokata et al. (1992) identified homozygosity for a nucleotide transition in the XPA gene, resulting in an arg207-to-ter (R207X) substitution.


.0006 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, TYR116TER
  
RCV000001052

In 2 unrelated Japanese patients with severe XPA (278700), Satokata et al. (1992) identified a T-to-A transversion in the XPA gene, resulting in a tyr116-to-ter (Y116X) substitution. One patient was compound heterozygous for this mutation and for the splice site mutation in intron 3 (611153.0001), and the other patient was heterozygous for this mutation and homozygous for the splice site mutation.

Maeda et al. (1995) reported that a patient who was homozygous for the Y116X mutation had never walked unaided. This was in contrast to the finding in patients homozygous for the common splice site mutation in intron 3 who could walk unaided until 7-16 years of age.


.0007 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, IVS1DS, T-G, +2
  
RCV000001053

In a Japanese patient with XPA (278700), Tanioka et al. (2005) identified compound heterozygosity for 2 mutations in the XPA gene: a T-to-G transversion in intron 1, resulting in a splice site defect, and the common IVS3 splice site mutation (611153.0001). The intron 1 mutation resulted in 2 different mRNA transcripts that were both predicted to cause frameshift and premature termination. XPA protein was not detected in patient cells, and UV-induced unscheduled DNA synthesis was 4.75% of normal. The patient had photosensitivity but had not developed neurologic involvement by age 6 years.


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  39. Tanaka, K., Miura, N., Satokata, I., Miyamoto, I., Yoshida, M. C., Satoh, Y., Kondo, S., Yasui, A., Okayama, H., Okada, Y. Analysis of a human DNA excision repair gene involved in group A xeroderma pigmentosum and containing a zinc-finger domain. Nature 348: 73-76, 1990. [PubMed: 2234061, related citations] [Full Text]

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Cassandra L. Kniffin - updated : 10/1/2007
Patricia A. Hartz - updated : 10/1/2007
Creation Date:
Cassandra L. Kniffin : 6/29/2007
carol : 03/15/2021
alopez : 10/05/2016
mcolton : 06/03/2015
carol : 9/12/2013
carol : 1/12/2010
carol : 4/14/2009
wwang : 10/9/2007
ckniffin : 10/1/2007
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carol : 7/12/2007
carol : 7/12/2007
ckniffin : 7/6/2007

* 611153

XPA, DNA DAMAGE RECOGNITION AND REPAIR FACTOR; XPA


Alternative titles; symbols

XPA GENE
XPA COMPLEMENTING GENE; XPAC


HGNC Approved Gene Symbol: XPA

SNOMEDCT: 43477006;  


Cytogenetic location: 9q22.33     Genomic coordinates (GRCh38): 9:97,654,398-97,697,340 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
9q22.33 Xeroderma pigmentosum, group A 278700 Autosomal recessive 3

TEXT

Description

The XPA gene encodes a protein involved in DNA excision repair (Tanaka et al., 1990).


Cloning and Expression

Tanaka et al. (1989, 1990) cloned a mouse gene that restored UV light-resistance in 2 cell lines from patients with xeroderma pigmentosum complementation group A (XPA; 278700). No correction was observed in relation to other XP groups. Tanaka et al. (1989) concluded that they had succeeded in cloning the mouse homolog of the gene that is mutant in XPA.

Tanaka et al. (1990) cloned a cDNA corresponding to the human XPA gene. The deduced 273-amino acid protein has a calculated molecular mass of 31 kD. The human protein is 95% similar to the mouse protein and contains several alpha-helices and a zinc-finger motif, consistent with a DNA-binding protein. Two mRNAs, 1.3-1.4 kb and 1.0-1.1 kb, were detected in normal human cells. Sequence analysis identified a truncated XPA protein that could be translated from an ATG present at position 176, which retained sufficient function to partially restore the DNA repair defect in XPA cells. A 1.0-1.1-kb mouse Xpa mRNA was also identified. Expression of XPA cDNA conferred UV resistance to several cells derived from patients with xeroderma pigmentosum complementation group A, but not with other XP complementation groups.

Shimamoto et al. (1991) compared the homologous Xpa genes in chicken, Xenopus laevis, and Drosophila melanogaster with the human gene. A high level of conservation was found in the COOH-terminal domain where the frequency of identical amino acids was about 50% with preservation of the zinc finger motif, suggesting that this portion of the gene plays an important role in the function of the protein.

In the yeast Saccharomyces cerevisiae, any one of 5 genes, RAD1, RAD2, RAD3, RAD4, and RAD10, causes a total defect in the incision step of excision repair of DNA damaged by ultraviolet light and an extreme sensitivity to ultraviolet light. Bankmann et al. (1992) reported the characterization of the yeast RAD14 gene and found that it encodes a highly hydrophilic 247-residue protein containing zinc finger motifs with high similarity to the protein encoded by the human XPA gene. Studies with a RAD14 deletion mutation indicated the absolute requirement of the gene in the DNA incision process.


Gene Structure

Miyamoto et al. (1992) determined that the XPA gene contains 6 exons. Studies using site-directed mutagenesis showed that the nuclear localization signal of the XPA gene is located in the region encoded by exon 1, whereas exons 2 through 6 are essential for the DNA repair function. All 4 cysteines forming a zinc finger structure and also the glutamic acid cluster in the region encoded by exon 2 were found to be important for DNA repair function.


Mapping

Using mouse-human hybrid cell lines, Kaur and Athwal (1989) achieved complementation of the repair defect in xeroderma pigmentosum group A cells by the transfer of human chromosome 9. Henning et al. (1990) showed that microcell-mediated transfer of a single rearranged human chromosome from a human-mouse somatic cell hybrid resulted in specific complementation of defective repair and UV sensitivity in XPA cells. Cytogenetic analysis and Southern blot analysis localized the XPA gene to chromosome 9q22.2-q34.3.

Using microcell fusion studies, Ishizaki et al. (1990) demonstrated that 7 of 11 recipient XP clones became UV-resistant after transfer of chromosome 9. Southern hybridization analysis confirmed that at least part of a normal human chromosome 9 had been transferred into recipient clones.

Tanaka et al. (1990) localized the human and mouse XPAC genes to 9q34.1 and 4C2, respectively, by in situ hybridization.

Farndon et al. (1994) stated that the XPAC gene, like the basal cell nevus syndrome gene (NBCCS; 109400), the gene for self-healing squamous epithelioma (MSSE; 132800), and the group C Fanconi anemia gene (FACC; 227645), all map to 9q22.3-q31. Lench et al. (1996) created an EST- and STS-based YAC contig map of human 9q22.3 and showed that it contains the following genes in this order, from centromere to telomere: TMOD (190930), XPA, ALDOB (612724), BAAT (602938). The 4 genes are located in a syntenic region of mouse chromosome 4 and are arranged in the same order as their human counterparts on 9q.


Gene Function

Li et al. (1994) demonstrated that the XPA protein associates in a specific manner with ERCC1 (126380). They suggested that one possible function of XPA is the loading and perhaps the orientation of an incision complex, containing ERCC1 and other factors, to the site of DNA damage. Park and Sancar (1994) concluded from their studies that XPA, ERCC1, and ERCC4 (133520) proteins form a ternary complex that participates in both damage recognition and incision activities. Using site-specific mutagenesis, Li et al. (1995) found that the association between XPA and ERCC1 is a required step in the nucleotide excision repair pathway and that the probable role of the interaction is to recruit the ERCC1 incision complex to the damaged site.

Excision repair of bulky DNA adducts, such as those formed by the cancer chemotherapy agent cisplatin, appears to be mediated by an aggregate of genes, with the XPAC and ERCC1 proteins being involved in DNA damage recognition and excision. Dabholkar et al. (1994) assessed mRNA levels of ERCC1 and XPAC in malignant ovarian cancer tissues from 28 patients that were harvested before the administration of platinum-based chemotherapy. They found that cancer tissues from patients whose tumors were clinically resistant to therapy showed greater levels of total ERCC1 mRNA, full-length transcript of ERCC1 mRNA, and XPAC mRNA, as compared with tumor tissues from those individuals clinically sensitive to therapy. The number of patients in the 2 groups were 13 and 15, respectively.

Volker et al. (2001) described the assembly of the NER complex in normal and repair-deficient (xeroderma pigmentosum) human cells by employing a novel technique of local ultraviolet irradiation combined with fluorescent antibody labeling. The damage-recognition complex XPC (613208)-HR23B (RAD23B; 600062) appeared to be essential for the recruitment of all subsequent NER factors in the preincision complex, including transcription repair factor TFIIH (see 189972). Volker et al. (2001) found that XPA associates relatively late, is required for anchoring of ERCC1-XPF, and may be essential for activation of the endonuclease activity of XPG (133530). These findings identified XPC as the earliest known NER factor in the reaction mechanism, gave insight into the order of subsequent NER components, provided evidence for a dual role of XPA, and supported a concept of sequential assembly of repair proteins at the site of damage rather than a preassembled repairosome.

By yeast 2-hybrid analysis, Nitta et al. (2000) identified XAB1 (611479) as an XPA-binding protein. Mutation analysis showed that XAB1 specifically bound residues 30 to 34 of XPA.

Lembo et al. (2003) found that coexpression of XPA, MBD2 (603547), and XAB1 in 293T cells resulted in their coimmunoprecipitation, and the results suggested that XAB1 functions as a bridge between MBD2 and XPA.


Molecular Genetics

In multiple cell lines derived from Japanese patients with XP group A, Tanaka et al. (1990) identified a homozygous mutation in the XPA gene (611153.0001).

Cleaver et al. (1995) reported novel deletion and insertion mutations in a family with 2 daughters previously classified as homozygous for defects in the XPA gene (Davis et al., 1994). One mutation was a 20-bp deletion in exon 4; the other was a 1-bp adenine insertion in exon 5 in a region normally consisting of 6 adenines. Owing to the presence of multiple adenines in affected regions of both alleles, the precise bases that were lost or inserted to generate the observed alterations were ambiguous. The 20-nucleotide deletion was found to be from the maternal allele.

In patients with XPA, Satokata et al. (1992, 1992) identified homozygous or compound heterozygous mutations in the XPA gene (611153.0002-611153.0006).

Cleaver et al. (1999) reviewed mutations identified in the XPA gene and their population frequencies.


Genotype/Phenotype Correlations

States et al. (1998) performed a mutation analysis on XPA cell lines from 19 American and European patients. Most mutations were deletions and splice site mutations, observed previously in other XPA patients in exon 3, intron 3, or exon 4, that resulted in frameshifts within the DNA-binding region. One new mutation was a point mutation within intron 3 causing a new splice acceptor site that may compete with the original splice acceptor site. Mutations in the DNA-binding region of XPA were from patients with the more severe disease often associated with neurologic complications, whereas mutations in the C terminus of the protein, which interacts with the TFIIH transcription factor, were from patients with milder skin disease only. The rarity of naturally occurring missense mutations in the DNA-binding region of XPA suggests that amino acid changes may be sufficiently tolerated such that patients could have mild symptoms and escape detection.


Nomenclature

Lehmann et al. (1994) proposed the following nomenclature scheme for human DNA repair genes: (1) For xeroderma pigmentosum genes, the final C from the XPAC, XPBC, etc., genes should be omitted. The final C should be retained in excision repair cross-complementing (ERCC) genes; (2) where an ERCC gene has been found to be unequivocally identical to a xeroderma pigmentosum, Cockayne syndrome, or trichothiodystrophy (TTD; 601675) gene, the name should eventually be replaced by the corresponding XP, CS, or TTD gene. Thus, ERCC2, ERCC3, and ERCC6 would become the XPD, XPB, and CSB genes, respectively.


Animal Model

Nakane et al. (1995) established Xpa-deficient mice by gene targeting of mouse embryonic stem cells. The Xpa-deficient mice showed neither obvious physical abnormalities nor pathologic alterations, but were defective in nucleotide-excision repair and highly susceptible to ultraviolet-B- and 9,10-dimethyl-1,2-benz[a]anthracene-induced skin carcinogenesis. The findings provided in vivo evidence that the Xpa protein protects mice from carcinogenesis initiated by ultraviolet or chemical carcinogen. Comparable findings were independently reported by de Vries et al. (1995).

Mouse models of XPA have been established by gene targeting and found not to develop clearly detectable neurologic abnormalities, although they do show susceptibility to UV- and chemical carcinogen-induced skin cancer. Similarly, mice who are rendered deficient in the CSB gene (609413), which is deficient in group B Cockayne syndrome (133540), show only a mild neurologic phenotype. Murai et al. (2001) produced mice lacking both the Xpa and the Csb genes and found growth retardation and abnormal behavior closely resembling symptoms observed in human XPA and/or CSB patients at an early postnatal stage. The cerebellum was hypoplastic and showed impaired foliation and stunted Purkinje cell dendrites. The findings suggested that Xpa and Csb have additive roles in the mouse nervous system and support a crucial role for these 2 genes in normal brain development.

De Boer et al. (2002) found that mice with an ERCC2 mutation (R722W; 126340.0014) had many symptoms of premature aging, including osteoporosis and kyphosis, osteosclerosis, early graying, cachexia, infertility, and reduced life span. Trichothiodystrophy (TTD; 601675) 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.


History

Early Mapping Studies

Using hamster-human hybrid cells with various chromosomal constitution, Keijzer et al. (1984) excluded linkage of XP group A to the X chromosome, which had been thought to be involved (Stefanini et al., 1982), and found linkage to chromosome 1q. Keijzer et al. (1987) fused human, Chinese hamster or Chinese hamster/human hybrid cytoplasts with UV-irradiated XPA cells. Unscheduled DNA synthesis in the XP nucleus showed correction of the defect immediately after fusion of human cytoplasts, whereas the Chinese hamster cytoplasts did not show this rapid increase in excision repair. The results obtained after fusion of cytoplasts isolated from a panel of 26 Chinese hamster-human hybrids showed that chromosome 1q42-qter contained genetic information necessary for the rapid correction of the XP defect. However, correction was also observed with cytoplasts from a hybrid cell made between a Chinese hamster cell and an XP cell containing human chromosome 1, suggesting that the correcting factor consisted of both human and Chinese hamster components and that the gene mapped to chromosome 1 may not be the one that is mutated in XP of the A group. In fact, the mapping to chromosome 1 was never confirmed (Cleaver, 1993) and the gene was subsequently mapped to chromosome 9. Kaur et al. (1992) observed partial complementation in XP group A cells by a gene that mapped to human chromosome 8.


ALLELIC VARIANTS 7 Selected Examples):

.0001   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, IVS3AS, G-C
SNP: rs750218942, gnomAD: rs750218942, ClinVar: RCV000246304, RCV001063951, RCV001255518

In 19 of 20 Japanese patients with xeroderma pigmentosum complementation group A (278700), Tanaka et al. (1990) identified a G-to-C transversion at the 3-prime splice acceptor site of intron 3 of the XPA gene. Satokata et al. (1990) found that the G-to-C transversion abolished the canonical 3-prime splice site and created 2 abnormally spliced mRNA forms. The larger form was identical with normal mRNA except for a dinucleotide deletion at the 5-prime end of exon 4, which resulted in a frameshift with premature termination of translation in exon 4. The smaller form had a deletion of the entire exon 3 and the dinucleotide at the 5-prime end of exon 4. A single base substitution creates a new cleavage site for the restriction endonuclease AlwNI.

Using the AlwNI RFLP, Satokata et al. (1990) found that 16 of 21 unrelated Japanese patients with XP were homozygous and 4 were heterozygous for this mutation. However, 11 Caucasians and 2 blacks with group A XP did not have this mutant allele. Kore-eda et al. (1992) demonstrated the usefulness of the polymerase chain reaction (PCR) followed by search for the AlwNI RFLP in the diagnosis of XPA.

Cleaver et al. (1995) stated that homozygosity for the G-to-C transversion at the 3-prime acceptor site of intron III/exon IV of the XPA gene represents 80 to 90% of Japanese patients with XPA.

Maeda et al. (1995) reported that patients who were homozygous for the common splice site mutation in intron 3 could walk unaided until 7-16 years of age.


.0002   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, CYS108PHE
SNP: rs104894131, gnomAD: rs104894131, ClinVar: RCV000001048

In a cell line derived from a patient with XPA (278700), Satokata et al. (1992) found compound heterozygosity for 2 mutations in the XPA gene: a 323G-T transversion resulting in a cys108-to-phe (C108F) substitution that disrupted a putative zinc finger domain, and a 5-bp deletion (611153.0003).


.0003   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, 5-BP DEL
SNP: rs1200172747, gnomAD: rs1200172747, ClinVar: RCV000001049, RCV000780797, RCV001057886

In a cell line derived from a patient with XPA (278700), Satokata et al. (1992) found compound heterozygosity for 2 mutations in the XPA gene: a 5-bp deletion causing a frameshift and premature termination, and C108F (611153.0002).


.0004   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, ARG228TER
SNP: rs104894132, gnomAD: rs104894132, ClinVar: RCV000001050, RCV000781924, RCV000815514

Satokata et al. (1992) described a C-to-T transition in exon 6 of the XPA gene, resulting in an arg228-to-ter (R228X) substitution, as a cause of XPA (278700). The mutation created a new cleavage site for the restriction endonuclease HphI. Of 21 unrelated XPA patients examined, 1 was homozygous for this mutation and 3 were compound heterozygotes for this mutation and a splice site mutation in intron 3 (611153.0001). The homozygous patient was atypical with mild skin symptoms and minimal neurologic abnormalities.

Xeroderma pigmentosum patients in Tunisia who belong to the genetic complementation group A have milder skin symptoms than do Japanese XPA patients. Nishigori et al. (1993) found that 6 of 7 Tunisian XPA patients had the R228X mutation.

Maeda et al. (1995) reported that a patient who was homozygous for the R228X mutation could walk unaided without any difficulty until the age of 21 years.


.0005   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, ARG207TER
SNP: rs104894133, gnomAD: rs104894133, ClinVar: RCV000001051, RCV000657642, RCV001420782

In a Palestinian patient with severe XPA (278700), Satokata et al. (1992) identified homozygosity for a nucleotide transition in the XPA gene, resulting in an arg207-to-ter (R207X) substitution.


.0006   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, TYR116TER
SNP: rs104894134, gnomAD: rs104894134, ClinVar: RCV000001052

In 2 unrelated Japanese patients with severe XPA (278700), Satokata et al. (1992) identified a T-to-A transversion in the XPA gene, resulting in a tyr116-to-ter (Y116X) substitution. One patient was compound heterozygous for this mutation and for the splice site mutation in intron 3 (611153.0001), and the other patient was heterozygous for this mutation and homozygous for the splice site mutation.

Maeda et al. (1995) reported that a patient who was homozygous for the Y116X mutation had never walked unaided. This was in contrast to the finding in patients homozygous for the common splice site mutation in intron 3 who could walk unaided until 7-16 years of age.


.0007   XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A

XPA, IVS1DS, T-G, +2
SNP: rs1587755557, ClinVar: RCV000001053

In a Japanese patient with XPA (278700), Tanioka et al. (2005) identified compound heterozygosity for 2 mutations in the XPA gene: a T-to-G transversion in intron 1, resulting in a splice site defect, and the common IVS3 splice site mutation (611153.0001). The intron 1 mutation resulted in 2 different mRNA transcripts that were both predicted to cause frameshift and premature termination. XPA protein was not detected in patient cells, and UV-induced unscheduled DNA synthesis was 4.75% of normal. The patient had photosensitivity but had not developed neurologic involvement by age 6 years.


See Also:

Keijzer et al. (1982); Mori et al. (1993); Rinaldy et al. (1988); Schultz et al. (1985)

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Contributors:
Cassandra L. Kniffin - updated : 10/1/2007
Patricia A. Hartz - updated : 10/1/2007

Creation Date:
Cassandra L. Kniffin : 6/29/2007

Edit History:
carol : 03/15/2021
alopez : 10/05/2016
mcolton : 06/03/2015
carol : 9/12/2013
carol : 1/12/2010
carol : 4/14/2009
wwang : 10/9/2007
ckniffin : 10/1/2007
mgross : 10/1/2007
carol : 7/12/2007
carol : 7/12/2007
ckniffin : 7/6/2007