Alternative titles; symbols
HGNC Approved Gene Symbol: POLE
Cytogenetic location: 12q24.33 Genomic coordinates (GRCh38): 12:132,623,762-132,687,342 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.33 | {Colorectal cancer, susceptibility to, 12} | 615083 | Autosomal dominant | 3 |
| FILS syndrome | 615139 | Autosomal recessive | 3 | |
| IMAGE-I syndrome | 618336 | Autosomal recessive | 3 |
The POLE gene encodes the catalytic subunit of DNA polymerase epsilon (EC 2.7.7.7), one of the 4 nuclear DNA polymerases in eukaryotic cells. The mammalian enzyme is involved in DNA repair and possibly also in replication of chromosomal DNA. For additional background information on DNA polymerases, see 174761.
Li et al. (1997) stated that active POLE protein consists of a 261-kD catalytic subunit tightly bound to a 55-kD accessory subunit (602670). Li et al. (1997) cloned cDNAs encoding both subunits. The cDNA of the catalytic subunit predicted a protein of 2,285 amino acids.
Szpirer et al. (1994) assigned the gene for the large subunit of POLE to chromosome 12 in both human and rat by Southern blot analysis of genomic DNA from mouse/human and mouse/rat somatic cell hybrid panels using a human cDNA probe. The human gene was then regionally localized to 12q24.3 by fluorescence in situ hybridization. POLE is closely linked to the gene for hepatocyte nuclear factor-1 (HNF1A; 142410), a hepatic transcription factor. The 2 genes define a synteny group retained on human and rat chromosomes 12.
Goldsby et al. (1998) mapped the POLE gene to mouse chromosome 5.
Susceptibility to Colorectal Cancer
In affected members of a family with susceptibility to colorectal cancer (CRCS12; 615083), Palles et al. (2013) identified a heterozygous missense mutation in the POLE gene (L424V; 174762.0001) affecting a highly conserved residue in the exonuclease (proofreading) domain. The L424V mutation was subsequently identified in 12 more families with early-onset colorectal adenomas and carcinomas. The phenotype was compatible with autosomal dominant inheritance of a high-penetrance predisposition to the development of colorectal adenomas and carcinoma, with a variable tendency to develop multiple and large tumors. The histologic features of the tumors were unremarkable, and all were microsatellite stable. Some tumors had additional somatic mutations, for example, in the APC (611731) or KRAS (190070) genes. In addition to germline POLE mutations, Palles et al. (2013) identified somatic POLE mutations, many affecting the exonuclease domain, in 15 colorectal cancers from a large database. All of these tumors had additional somatic mutations, most commonly in the APC gene. These findings suggested that the mechanism of tumorigenesis in POLE-mutated tumors is decreased fidelity of replication-associated polymerase proofreading, leading to an increased mutation rate.
Elsayed et al. (2015) identified heterozygosity for the L424V mutation in the POLE gene in 3 (0.25%) of 1,188 Dutch index patients with polyposis or familial colorectal cancer. In 1 patient, the mutation occurred de novo. Tumor tissue samples available from 3 patients from 2 families showed microsatellite instability and were found to have somatic mutations in the MSH2 (609309) and/or MSH6 (600678) genes. The findings indicated that POLE DNA analysis is warranted in microsatellite-unstable colorectal cancer, especially in the absence of a germline variant in DNA mismatch repair genes.
Bellido et al. (2016) sequenced the exonuclease domains of POLE and POLD1 (174761) in 529 kindreds, 441 with familial nonpolyposis CRC and 88 with polyposis. They identified 7 novel or rare variants. In addition to the POLE L424V recurrent mutation in a patient with polyposis, CRC, and oligodendroglioma, Bellido et al. (2016) identified 6 novel or rare POLD1 variants in nonpolyposis CRC families.
FILS Syndrome
By homozygosity mapping followed by candidate gene sequencing of a consanguineous French family with facial dysmorphism, immunodeficiency, livedo, and short stature (FILS; 615139), Pachlopnik Schmid et al. (2012) identified a homozygous splice site mutation in the POLE1 gene (174762.0002). PCR analysis of patient T cells showed 2 types of POLE1 transcripts, wildtype (10%) and a mutant transcript lacking exon 34 (90%). Studies of patient T cells, B cells, chondrocytes, and osteoblasts showed an impairment in cell proliferation and in G1- to S-phase progression.
In a 2-year-old Palestinian girl (CMH812) with FILS, Thiffault et al. (2015) identified homozygosity for the same POLE splice site mutation (c.4444+32G-A) found in the French family reported by Pachlopnik Schmid et al. (2012).
IMAGEI Syndrome
In 15 patients from 12 families with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (IMAGEI; 618336), Logan et al. (2018) identified compound heterozygosity for mutations in the POLE gene. All patients shared the same intronic variant (c.1686+32C-G; 174762.0003) as part of a common haplotype, in combination with different presumed loss-of-function mutations (see, e.g., 174762.0004-174762.0007). Analysis of patient fibroblasts showed cellular deficiency of POLE and delayed S-phase progression.
In affected members of a family with susceptibility to colorectal cancer-12 (CRCS12; 615083), Palles et al. (2013) identified a heterozygous 1270C-G transversion in the POLE gene, resulting in a leu424-to-val (L424V) substitution at a highly conserved residue in the active site of the exonuclease (proofreading) domain. The mutant mRNA was stably expressed. Molecular modeling using yeast structures indicated that the L424V mutation will distort the packing of helices involved at the exonuclease active site, likely affecting nuclear activity. The mutation was identified by linkage analysis combined with whole-genome sequencing. Direct screening for this mutation in 3,805 individuals of European ancestry with a familial colorectal cancer, multiple adenomas, and early-onset disease resulted in the identification of 12 additional unrelated probands with the mutation. The mutation was not found in 6,721 control individuals or in 10,755 control exomes. The mutation segregated with the phenotype in each of the families; there was no evidence for a common ancestor. The phenotype was compatible with autosomal dominant inheritance of a high-penetrance predisposition to the development of colorectal adenomas and carcinomas, with a variable tendency to develop multiple and large tumors. The histologic features of the tumors were unremarkable, and all were microsatellite stable. Some tumors had additional somatic mutations, for example, in the APC (611731) or KRAS (190070) genes.
Valle et al. (2014) identified a de novo heterozygous L424V mutation in the POLE gene in a 28-year-old woman with polyposis and colorectal cancer. No loss of heterozygosity at the POLE chromosomal region was found in tumor DNA. This patient was ascertained from a cohort of 858 Spanish probands with familial/early-onset CRC who underwent screening of the POLE gene, thus accounting for 0.12% of the total.
Elsayed et al. (2015) identified heterozygosity for the c.1270C-G transversion (c.1270C-G, NM_006231.2) in the POLE gene, resulting in a L424V mutation, in 3 (0.25%) of 1,188 Dutch index patients with polyposis or familial colorectal cancer. In 1 patient, the mutation occurred de novo. Tumor tissue samples available from 3 patients from 2 families showed microsatellite instability and were found to have somatic mutations in the MSH2 (609309) and/or MSH6 (600678) genes. The findings indicated that POLE DNA analysis is warranted in microsatellite-unstable colorectal cancer, especially in the absence of a germline variant in DNA Mismatch repair genes.
By homozygosity mapping followed by candidate gene sequencing of a consanguineous French family with facial dysmorphism, immunodeficiency, livedo, and short stature (FILS; 615139), Pachlopnik Schmid et al. (2012) identified a homozygous A-to-G transition in intron 34 of the POLE1 gene, resulting in the skipping of exon 34, a frameshift, premature termination at position 1561, and a protein lacking the C terminus (g.G4444+3A-G). Unaffected parents were heterozygous for the mutation, which was not found in several large control databases. PCR analysis of patient T cells showed 2 types of POLE1 transcripts, wildtype (10%) and a mutant transcript lacking exon 34 (90%). There was severely decreased expression of full-length POLE1 in patient cells. In addition, there was decreased protein expression of POLE2 (602670), supporting a role of POLE1 in stabilizing POLE2. Finally, studies of patient T cells, B cells, chondrocytes, and osteoblasts showed an impairment in cell proliferation and in G1- to S-phase progression of the cell cycle. Expression of wildtype POLE1 restored S-phase progression in patient cells.
In 15 patients from 12 families with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (IMAGEI; 618336), including an Australian man (P13) originally reported by Pedreira et al. (2004) and 2 Australian sisters (P11 and P12) previously described by Tan et al. (2006), Logan et al. (2018) identified compound heterozygosity for mutations in the POLE gene. All patients shared the same splice site variant in intron 15 (c.1686+32C-G, NM_006231.3) as part of a common haplotype, in combination with different loss-of-function mutations (see, e.g., 174762.0004-174762.0007). Analysis of fibroblasts from patients P1 and P3 demonstrated that the c.1686+32C-G variant markedly impaired splicing of the usual exon 15 donor site, resulting in preferential use of a downstream alternate splice donor site in intron 15, although some canonical splicing also occurred. The inclusion of 47 bp of intronic DNA in the variant transcript causes a frameshift predicted to result in a premature stop codon (Asn563ValfsTer16); the authors noted that any translated protein would be nonfunctional, given that the frameshift occurs at the start of the polymerase catalytic domain. In the 2 Australian sisters (P11 and P12), the second mutation was a 1-bp deletion (c.5265delG; 174762.0004) in exon 39, causing a frameshift predicted to result in a premature termination codon (Ile1756SerfsTer5); in 3 patients from the US and Ireland (P7, P8, and P9), it was a c.1A-T transversion in exon 1 of the POLE gene, resulting in a met1-to-? (Met1?;174762.0005) substitution; in the 22-year-old Australian man (P13), it was a c.2049C-G transversion in exon 19, resulting in a tyr683-to-ter (Y683X; 174762.0006) substitution; and in a 39-year-old woman (P10), it was a c.3019G-C transversion in exon 25, resulting in an ala1007-to-pro (A1007P) substitution at a highly conserved residue within the polymerase domain. All of the variants were rare, with minor allele frequencies less than 0.000071 in the European (non-Finnish) population in the gnomAD database, and in the 11 families for which parental DNA was available, the unaffected parents were each heterozygous for 1 of the mutations. Immunoblot analysis of total protein extracts from fibroblasts from P1 and P3 showed markedly depleted POLE1 levels, to approximately 5 to 11% of those of controls. Time-course fluorescence-activated cell sorting analysis demonstrated delayed cell-cycle progression of BrdU-labeled primary fibroblasts from patients P1 ad P3, indicative of impaired S-phase progression. Logan et al. (2018) concluded that POLE deficiency causes reduced levels of chromatin-loaded POLE complexes, resulting in replication stress arising from reduced numbers of active replication origins.
For discussion of the 1-bp deletion (c.5265delG, NM_006231.3) in exon 39 of the POLE gene, causing a frameshift predicted to result in a premature termination codon (Ile1756SerfsTer5) that was found in compound heterozygous state in 2 Australian sisters (P11 and P12) with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (IMAGEI; 618336) by Logan et al. (2018), see 174762.0003.
For discussion of the c.1A-T transversion (c.1A-T, NM_006231.3) in exon 1 of the POLE gene, resulting in a met1-to-? (Met1?) substitution, that was found in compound heterozygous state in 3 patients (P7, P8, and P9) with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (IMAGEI; 618336) by Logan et al. (2018), see 174762.0003.
For discussion of the c.2049C-G transversion (c.2049C-G, NM_006231.3) in exon 19 of the POLE gene, resulting in a tyr683-to-ter (Y683X) substitution, that was found in compound heterozygous state in a 22-year-old Australian man (P13) with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (IMAGEI; 618336) by Logan et al. (2018), see 174762.0003.
For discussion of the c.3019G-C transversion (c.3019G-C, NM_006231.3) in exon 25 of the POLE gene, resulting in an ala1007-to-pro (A1007P) substitution, that was found in compound heterozygous state in a 39-year-old woman (P10) with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (IMAGEI; 618336) by Logan et al. (2018), see 174762.0003.
Bellido, F., Pineda, M., Aiza, G., Valdes-Mas, R., Navarro, M., Puente, D. A., Pons, T., Gonzalez, S., Iglesias, S., Darder, E., Pinol, V., Soto, J. L., Valencia, A., Blanco, I., Urioste, M., Brunet, J., Lazaro, C., Capella, G., Puente, X. S., Valle, L. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet. Med. 18: 325-332, 2016. [PubMed: 26133394] [Full Text: https://doi.org/10.1038/gim.2015.75]
Elsayed, F. A., Kets, C. M., Ruano, D., van den Akker, B., Mensenkamp, A. R., Schrumpf, M., Nielsen, M., Wijnen, J. T., Tops, C. M., Ligtenberg, M. J., Vasen, H. F. A., Hes, F. J., Morreau, H., van Wezel, T. Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Europ. J. Hum. Genet. 23: 1080-1084, 2015. [PubMed: 25370038] [Full Text: https://doi.org/10.1038/ejhg.2014.242]
Goldsby, R. E., Singh, M., Preston, B. D. Mouse DNA polymerase epsilon gene (Pole) maps to chromosome 5. Mammalian Genome 9: 91-92, 1998. [PubMed: 9434959] [Full Text: https://doi.org/10.1007/s003359900692]
Li, Y., Asahara, H., Patel, V. S., Zhou, S., Linn, S. Purification, cDNA cloning, and gene mapping of the small subunit of human DNA polymerase epsilon. J. Biol. Chem. 272: 32337-32344, 1997. [PubMed: 9405441] [Full Text: https://doi.org/10.1074/jbc.272.51.32337]
Logan, C. V., Murray, J. E., Parry, D. A., Robertson, A., Bellelli, R., Tarnauskaite, Z., Challis, R., Cleal, L., Borel, V., Fluteau, A., Santoyo-Lopez, J., SGP Consortium, and 35 others. DNA polymerase epsilon deficiency causes IMAGe syndrome with variable immunodeficiency. Am. J. Hum. Genet. 103: 1038-1044, 2018. [PubMed: 30503519] [Full Text: https://doi.org/10.1016/j.ajhg.2018.10.024]
Pachlopnik Schmid, J., Lemoine, R., Nehme, N., Cormier-Daire, V., Revy, P., Debeurme, F., Debre, M., Nitschke, P., Bole-Feysot, C., Legeai-Mallet, L., Lim, A., de Villartay, J.-P., Picard, C., Durandy, A., Fischer, A., de Saint Basile, G. Polymerase epsilon-1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ('FILS syndrome'). J. Exp. Med. 209: 2323-2330, 2012. [PubMed: 23230001] [Full Text: https://doi.org/10.1084/jem.20121303]
Palles, C., Cazier, J.-B., Howarth, K. M., Domingo, E., Jones, A. M., Broderick, P., Kemp, Z., Spain, S. L., Guarino, E., Salguero, I., Sherborne, A., Chubb, D., and 27 others. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature Genet. 45: 136-144, 2013. Note: Erratum: Nature Genet. 45: 713 only, 2013. [PubMed: 23263490] [Full Text: https://doi.org/10.1038/ng.2503]
Pedreira, C. C., Savarirayan, R., Zacharin, M. R. IMAGe syndrome: a complex disorder affecting growth, adrenal and gonadal function, and skeletal development. J. Pediat. 144: 274-277, 2004. [PubMed: 14760276] [Full Text: https://doi.org/10.1016/j.jpeds.2003.09.052]
Szpirer, J., Pedeutour, F., Kesti, T., Riviere, M., Syvaoja, J. E., Turc-Carel, C., Szpirer, C. Localization of the gene for DNA polymerase epsilon (POLE) to human chromosome 12q24.3 and rat chromosome 12 by somatic cell hybrid panels and fluorescence in situ hybridization. Genomics 20: 223-226, 1994. [PubMed: 8020968] [Full Text: https://doi.org/10.1006/geno.1994.1156]
Tan, T. Y., Jameson, J. L., Campbell, P. E., Ekert, P. G., Zacharin, M., Savarirayan, R. Two sisters with IMAGE syndrome: cytomegalic adrenal histopathology, support for autosomal recessive inheritance and literature review. Am. J. Med. Genet. 140A: 1778-1784, 2006. [PubMed: 16835919] [Full Text: https://doi.org/10.1002/ajmg.a.31365]
Thiffault, I., Saunders, C., Jenkins, J., Raje, N., Canty, K., Sharma, M., Grote, L., Welsh, H. I., Farrow, E., Twist, G., Miller, N., Zwick, D., Zellmer, L., Kingsmore, S. F., Safina, N. P. A patient with polymerase E1 deficiency (POLE1): clinical features and overlap with DNA breakage/instability syndromes. BMC Med. Genet. 16: 31, 2015. Note: Electronic Article. [PubMed: 25948378] [Full Text: https://doi.org/10.1186/s12881-015-0177-y]
Valle, L., Hernandez-Illan, E., Bellido, F., Aiza, G., Castillejo, A., Castillejo, M.-I., Navarro, M., Segui, N., Vargas, G., Guarinos, C., Juarez, M., Sanjuan, X., and 14 others. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum. Molec. Genet. 23: 3506-3512, 2014. [PubMed: 24501277] [Full Text: https://doi.org/10.1093/hmg/ddu058]