Alternative titles; symbols
HGNC Approved Gene Symbol: XRCC4
Cytogenetic location: 5q14.2 Genomic coordinates (GRCh38) : 5:83,077,547-83,374,473 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q14.2 | Short stature, microcephaly, and endocrine dysfunction | 616541 | Autosomal recessive | 3 |
Eukaryotes use at least 2 pathways to repair DNA double-strand breaks: homologous recombination and nonhomologous end joining (NHEJ). The core NHEJ machinery includes XRCC4, DNA ligase IV (LIG4; 601837), and the DNA-dependent protein kinase complex, which consists of the DNA end-binding Ku70 (G22P1; 152690)/Ku80 (XRCC5; 194364) heterodimer and the catalytic subunit PRKDC (600899) (Mari et al., 2006).
XR-1 is a Chinese hamster ovary cell mutant that is unusually sensitive to killing by gamma rays in the G1 portion of the cell cycle, but has nearly normal resistance to gamma-ray damage in late S phase. This cell cycle sensitivity correlates with the mutant's inability to repair DNA double-strand breaks produced by ionizing radiation (IR) and restriction enzymes. Giaccia et al. (1990) identified a human gene on chromosome 5 that biochemically restored the hamster defect to wildtype levels of gamma-ray and bleomycin resistance, as well as restoring its proficiency to repair DNA double-stranded breaks. They designated the gene XRCC4.
In studies of somatic cell hybrids formed between XR-1 and human fibroblasts, Giaccia et al. (1990) mapped the human complementing gene XRCC4 to chromosome 5 by chromosome-segregation analysis. Otevrel and Stamato (1995) localized the XRCC4 gene to 5q13-q14 by studies based on a gamma-ray-resistant human:XR-1 hamster hybrid cell line containing fragments of human chromosome 5, which was fused with the gamma-ray-sensitive XR-1 mutant cell. After selection with the aminoglycoside G418, 2 of a total of 76 hybrids retained wildtype gamma-ray resistance. Fluorescence in situ hybridization analysis of normal human lymphocytes using DNA from the 2 resistant hybrids as probes produced a common region of hybridization at 5q13-q14. The gene was physically localized between D5S427 and D5S401 microsatellite markers and the cytologic assignment was confirmed using hamster/human hybrids containing known deletions in human chromosome 5.
Li et al. (1995) demonstrated that the human XRCC4 gene restores DNA double-strand break repair and the ability to support V(D)J recombination of transiently introduced substrates in the XR-1 CHO cell line. They showed that the corresponding gene is deleted in XR-1 cells. XRCC4 encodes a ubiquitously expressed product.
Using human and hamster cells, Mari et al. (2006) showed that Ku heterodimers on DNA ends were in dynamic equilibrium with Ku70/Ku80 in solution, suggesting that formation of the NHEJ complex is reversible. Accumulation of XRCC4 on DNA double-strand breaks depended on the presence of Ku70/Ku80, but not PRKDC. Mari et al. (2006) found that XRCC4 interacted directly with Ku70, and they hypothesized that XRCC4 serves as a flexible tether between Ku70/Ku80 and LIG4.
Yan et al. (2007) assessed whether the classical NHEJ pathway is critical for class switch recombination (CSR) by assaying CSR in Xrcc4- or Lig4 (601837)-deficient mouse B cells. Classical NHEJ indeed catalyzed CSR joins, because classical NHEJ-deficient B cells had decreased CSR and substantial levels of IgH locus (147100) chromosomal breaks. However, an alternative end joining pathway, which is markedly biased towards microhomology joins, supports CSR at unexpectedly robust levels in classical NHEJ-deficient B cells. In the absence of classical NHEJ, this alternative end joining pathway also frequently joins IgH locus breaks to other chromosomes to generate translocations.
Guirouilh-Barbat et al. (2007) studied NHEJ in Xrcc4- and Ku80-null XR-1 CHO cells and showed differences in the effects of these mutations. While significant end joining existed in Xrcc4-null cells due to the use of microhomologies distal from the double-strand break, the efficiency of NHEJ was reduced. In contrast, knockout of Ku80 barely affected the efficiency of end joining. In both mutant cell lines, however, the accuracy of end joining was reduced. Guirouilh-Barbat et al. (2007) concluded that the KU80/XRCC4 pathway is conservative and can accommodate non-fully complementary ends at the cost of limited mutagenesis.
Using dual- and quadruple-trap optical tweezers combined with fluorescence microscopy, Brouwer et al. (2016) demonstrated how human XRCC4, XLF (611290), and XRCC4-XLF complexes interact with DNA in real time. Brouwer et al. (2016) found that XLF stimulates the binding of XRCC4 to DNA, forming heteromeric complexes that diffuse swiftly along the DNA. Moreover, the authors found that XRCC4-XLF complexes robustly bridge 2 independent DNA molecules and that these bridges are able to slide along the DNA. These observations suggested that XRCC4-XLF complexes form mobile sleeve-like structures around DNA that can reconnect the broken ends very rapidly and hold them together. Brouwer et al. (2016) concluded that understanding the dynamics and regulation of this mechanism would lead to clarification of how NHEJ proteins are involved in generating chromosomal translocations.
In a 4-year-old Saudi Arabian girl with short stature and microcephaly (SSMED; 616541), Shaheen et al. (2014) identified homozygosity for a missense mutation in the XRCC4 gene (W43R; 194363.0001).
Murray et al. (2015) analyzed exome sequencing data from a cohort of 208 patients diagnosed with microcephalic primordial dwarfism and identified homozygosity for the XRCC4 W43R mutation in a Saudi Arabian boy with short stature, microcephaly, and lymphopenia. Resequencing of the XRCC4 gene in that cohort identified compound heterozygosity for truncating mutations in 5 more patients from 4 families (194363.0002-194363.0006). All mutations segregated with disease in the respective families.
In 50-year-old Italian twin brothers with short stature, cognitive impairment, hypergonadotropic hypogonadism, ataxia, and dilated cardiomyopathy, Bee et al. (2015) performed whole-exome sequencing and identified homozygosity for the previously reported R225X mutation in the XRCC4 gene (194363.0005).
In a brother and sister from rural Chile with short stature, microcephaly, hypergonadotropic hypogonadism, and early-onset metabolic syndrome, de Bruin et al. (2015) identified homozygosity for a missense mutation in the XRCC4 gene (D82E; 194363.0007) that segregated with disease in the family.
In 3 Turkish brothers with short stature, microcephaly, and mild developmental delay, Rosin et al. (2015) identified homozygosity for a missense mutation in XRCC4 (R161Q; 194363.0008) that was found to cause splicing defects. In a similarly affected Swiss girl, they identified compound heterozygosity for 2 previously reported XRCC4 mutations, a 1-bp deletion (c.25delC; 194363.0002) and a nonsense mutation (R275X; 194363.0003).
In a woman with short stature, microcephaly, hypothyroidism, diabetes mellitus, and progressive ataxia, Guo et al. (2015) identified compound heterozygosity for the R225X mutation (194363.0005) and a 1-bp deletion (c.760delG; 194363.0009) in XRCC4. Functional analysis in patient cells demonstrated a marked defect in double-strand break repair but efficient V(D)J recombination. Guo et al. (2015) concluded that this represents a separation-of-impact phenotype, in which marked deficiency in radiation-induced double-strand break repair can be uncoupled from defective V(D)J recombination.
To characterize the in vivo role of XRCC4, Gao et al. (1998) inactivated the XRCC4 gene in mice via gene-targeted mutation. They showed that XRCC4 deficiency in primary murine cells causes growth defects, premature senescence, IR sensitivity, and inability to support V(D)J recombination. In mice, XRCC4 deficiency causes late embryonic lethality accompanied by defective lymphogenesis and defective neurogenesis manifested by extensive apoptotic death of newly generated postmitotic neuronal cells. They also found similar neuronal developmental defects in embryos that lack DNA ligase IV (601837), an XRCC4-associated protein. These findings demonstrated that differentiating lymphocytes and neurons strictly require the XRCC4 and DNA ligase IV end-joining proteins.
Gao et al. (2000) bred mice homozygous for p53 (191170) deficiency with heterozygotes for XRCC4 deficiency to produce doubly homozygous mice. p53 deficiency rescued several aspects of the XRCC4-deficient phenotype, including embryonic lethality, neuronal apoptosis, and impaired cellular proliferation. However, there was no significant rescue of impaired V(D)J recombination or lymphocyte development. Although p53 deficiency allowed postnatal survival of XRCC4-deficient mice, they routinely succumbed to pro-B-cell lymphomas which had chromosomal translocations linking amplified c-myc oncogene (190080) and IgH locus (see 147100) sequences. Moreover, even XRCC4-deficient embryonic fibroblasts exhibited marked genomic instability including chromosomal translocations. Gao et al. (2000) concluded that their findings supported a crucial role for the nonhomologous end joining pathway as a caretaker of the mammalian genome, a role required both for normal development and for suppression of tumors. The tumor susceptibility phenotype of XRCC4 -/- p53 -/- mice contrasts with that of p53 -/- mice, which develop pro-T-cell lymphomas lacking translocations later in life.
Wang et al. (2008) found that conditional deletion of Xrcc4 in p53-deficient peripheral mouse B cells resulted in surface Ig-negative B-cell lymphomas. These lymphomas frequently harbored a reciprocal chromosomal translocation fusing IgH to Myc, as well as large chromosomal deletions or translocations involving IgK or IgL, with the latter fusing IgL to oncogenes or to IgH. Wang et al. (2008) concluded that XRCC4- and p53-deficient pro-B lymphomas routinely activate MYC by gene amplification, whereas XRCC4- and p53-deficient peripheral B-cell lymphomas routinely ectopically activate a single copy of MYC.
In a 4-year-old Saudi Arabian girl with severe short stature and microcephaly (SSMED; 616541), Shaheen et al. (2014) identified homozygosity for a c.127T-C transition (c.127T-C, NM_003401.3) in the XRCC4 gene, resulting in a trp43-to-arg (W43R) substitution at a highly conserved residue. Functional analysis in XRCC4-deficient fibroblasts demonstrated significant impairment to DNA damage repair following ionizing radiation.
In a Saudi Arabian boy with short stature, extreme microcephaly, and lymphopenia, Murray et al. (2015) identified homozygosity for the W43R mutation, located within the head domain of the XRCC4 gene. The mutation, which segregated with disease in the family, was reported to have an allele frequency of 3.3 x 10(-5) in control populations, with no homozygotes detected in the ExAC database. Expression and purification of recombinant XRCC4 in E. coli cells showed that the W43R substitution greatly reduces protein solubility compared to wildtype, and that the XRCC4 mutant is more prone to degradation. Analysis of circular dichroism spectra indicated that although the mutant protein is folded, it differs from wildtype. However, because in vitro ligation assays did not reveal any significant reduction in ligation efficiency with the mutant compared to wildtype, Murray et al. (2015) concluded that the W43R substitution more likely affects protein stability than directly affecting XRCC4 function. Immunoblotting of patient fibroblasts demonstrated strongly reduced levels of XRCC4 as well as of XLF (NHEJ1; 611290) and LIG4 (601837), indicating that the reduction in XRCC4 affects stability of the entire complex.
In complementation experiments involving the effect of various XRCC4 mutations on double-strand break repair, Guo et al. (2015) observed that the W43R mutant showed little complementation when expressed with the c.760delG mutant (194363.0009). They concluded that the W43R mutation impairs XRCC4 function.
In 4 children from 3 families with short stature and microcephaly (SSMED; 616541), Murray et al. (2015) identified compound heterozygosity for 2 mutations in the XRCC4 gene: a 1-bp deletion (c.25delC, NM_022550.2), predicted to result in a premature termination codon (His9ThrfsTer8), and another truncating mutation. Two Italian brothers and a 9-year-old French boy had a c.823C-T transition on the second allele, resulting in an arg275-to-ter (R275X; 194363.0003) substitution, whereas a 21-month-old boy from the United Kingdom had a c.-10-1G-T transversion involving the splice acceptor in exon 2 (194363.0004) on the second allele. Immunoblotting of fibroblasts from the UK patient demonstrated markedly reduced XRCC4 and LIG4 (601837) levels.
In a 14-year-old Swiss girl with short stature and microcephaly, Rosin et al. (2015) identified compound heterozygosity for the c.25delC and R275X mutations in the XRCC4 gene. Her parents were each heterozygous for 1 of the mutations.
For discussion of the c.823C-T transition (c.823C-T, NM_022550.2) in the XRCC4 gene, resulting in an arg275-to-ter (R275X) substitution, that was found in compound heterozygous state in patients with SSMED (616541) by Murray et al. (2015) and Rosin et al. (2015), see 194363.0002.
For discussion of the c.-10-1G-T transversion (c.-10-1G-T, NM_022550.2) in exon 2 of the XRCC4 gene that was found in compound heterozygous state in a 21-month-old boy from the United Kingdom with short stature and microcephaly (SSMD; 616541) by Murray et al. (2015), see 194363.0002.
In a 4-year-old Moroccan boy with short stature and microcephaly (SSMED; 616541), Murray et al. (2015) identified compound heterozygosity for 2 nonsense mutations in the XRCC4 gene: a c.673C-T transition (c.673C-T, NM_022550.2), resulting in an arg225-to-ter (R225X) substitution in the C-terminal domain, and a c.481C-T transition, resulting in an arg161-to-ter (R161X; 194363.0006) substitution within the coiled-coil domain.
In 50-year-old Italian twin brothers, born to first-cousin parents, with short stature, cognitive impairment, hypergonadotropic hypogonadism, axonal sensory neuropathy, and dilated cardiomyopathy, Bee et al. (2015) identified homozygosity for the R225X mutation in the XRCC4 gene, predicted to cause loss of one-third of the protein at the C terminus. Their unaffected father and sister were heterozygous for R225X; DNA was unavailable from their mother. Analysis of patient fibroblasts by quantitative PCR showed strong reduction in XRCC4 transcript levels compared to controls; XRCC4 protein was undetectable by Western blot analysis in total lysates obtained from patient fibroblasts, and this result was supported by immunofluorescence studies. Bee et al. (2015) noted that LIG4 (601837) was clearly present in patient lysates, although significantly reduced (40% of control mean). Gamma-irradiated mutant cells demonstrated reduction, but not abolition, of double-strand break repair.
In a woman (patient CSL16NG) with short stature, microcephaly, hypothyroidism, diabetes mellitus, progressive ataxia, and a low-grade thalamic glioma, who was originally reported as patient 3 by Neilan et al. (2008), Guo et al. (2015) identified compound heterozygosity for mutations in the XRCC4 gene: R225X and a 1-bp deletion (c.760delG; 194363.0009), causing a frameshift predicted to result in a premature termination codon (Asp254fsTer68). Allele-specific quantitative PCR revealed extremely low expression of the R225X allele, consistent with strong nonsense-mediated mRNA decay, whereas the other allele showed approximately 30% of the total XRCC4 expression level (rather than the expected 50% if fully expressed from 1 allele). Immunoblotting of patient fibroblasts demonstrated no detectable XRCC4, whereas immunofluorescence showed a low XRCC4 signal detectable in both the cytoplasm and nucleus; dilution studies with control fibroblasts suggested that there was less than 10% of the normal level of XRCC4 in patient cells. Immunoblotting also showed significantly reduced LIG4 in patient fibroblasts, with an estimated residual level between 5% and 15% of normal. Patient fibroblasts were markedly radiosensitive compared to controls, with diminished double-strand break repair; both the ability to synthesize DNA after irradiation and the repair of double-strand breaks were rescued by wildtype XRCC4. Plasmid double-strand break rejoining assays demonstrated that normal direct-end joining was nearly absent in patient cells, which instead used 6-bp microhomology at the junctions, consistent with loss of efficient nonhomologous end joining (NHEJ). Analysis of V(D)J recombination in patient cells showed enhanced fidelity compared to controls; however, an altered pattern of immunoglobulin class-switch recombination was also observed, suggesting that although the patient had a normal IgA level, there was a defect in the recombination process, which relies on classic NHEJ. Coexpression studies in HEK293 cells showed that the c.760delG mutant formed complexes with LIG4, demonstrating that the C terminus is dispensable for complex formation. In the presence of cyclohexamide, the c.760delG mutant was significantly degraded compared to wildtype, and the degradation was inhibited by the addition of proteasome inhibitors. The authors concluded that a major effect of the c.760delG mutation is greatly reduced protein stability caused by proteasomal degradation.
For discussion of the c.481C-T transition (c.481C-T, NM_022550.02) in the XRCC4 gene, resulting in an arg161-to-ter (R161X) substitution, that was found in compound heterozygous state in a Moroccan boy with SSMED (616541) by Murray et al. (2015), see 194363.0005.
In a brother and sister from rural Chile with short stature, microcephaly, hypergonadotropic hypogonadism, multinodular goiter, and early-onset metabolic syndrome (SSMED; 616541), de Bruin et al. (2015) identified homozygosity for a c.246T-G transversion in exon 3 of the XRCC4 gene, resulting in an asp82-to-glu (D82E) substitution predicted to create a novel 5-prime donor splice site that would cause aberrant splicing and an in-frame loss of 23 amino acids (Val83_Ser105del). The mutation segregated with the disorder in the family. RT-PCR analysis of patient cDNA confirmed generation of an approximately 900-bp product but not the approximately 980-bp product seen with wildtype XRCC4. Transfection studies in patient fibroblasts demonstrated severe impairment of the normal nonhomologous end-joining DNA damage-repair process, with almost exclusive use of an alternative microhomology-mediated end-joining process, compared to wildtype fibroblasts.
In 3 Turkish brothers with short stature, pronounced microcephaly, and mild psychomotor delay (SSMED; 616541), Rosin et al. (2015) identified homozygosity for a c.482G-A transition (c.482G-A, NM_022406) involving the last nucleotide in exon 4 of the XRCC4 gene, resulting in an arg161-to-gln (R161Q) substitution, but also predicted to disrupt the adjacent donor splice site of intron 4. Their first-cousin parents were heterozygous for the mutation, which was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Analysis of microsatellite markers in all family members confirmed homozygous haplotypes for the XRCC4 region on chromosome 5 in all affected individuals. By RT-PCR of patient cDNA followed by Sanger sequencing, 3 different transcripts were observed: a major transcript generated by complete skipping of exon 4, predicted to cause a frameshift and premature termination (Phe106IlefsTer1), a minor transcript due to complete skipping of exons 3 and 4, also resulting in premature termination (Val47AspfsTer5), and a correctly spliced minor transcript carrying the R161Q missense mutation. Western blot analysis of patient fibroblasts demonstrated a severe reduction in full-length XRCC4 protein compared to controls, consistent with RT-PCR results; however, a faint band of wildtype-size XRCC4 was detected, which was believed to represent full-length XRCC4 carrying the R161Q mutation. No expression of truncated XRCC4 protein was observed in patient fibroblasts or transfected HEK293 cells, implying protein instability and complete loss of function of the truncated variants. By MTT assay, Rosin et al. (2015) observed significantly higher cytotoxicity in patient fibroblasts than controls, suggesting that functional impairment of XRCC4 not only directly affects double-strand break repair, but also results in the induction of cell death if DNA lesions remain unrepaired.
For discussion of the c.760delG mutation in the XRCC4 gene that was found in compound heterozygous state in a woman with SSMED (616541) by Guo et al. (2015), see 194363.0005.
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