Alternative titles; symbols
HGNC Approved Gene Symbol: POLE2
Cytogenetic location: 14q21.3 Genomic coordinates (GRCh38): 14:49,643,555-49,688,214 (from NCBI)
The POLE2 gene encodes a subunit of the DNA polymerase-epsilon (POLE) complex, which is involved in DNA replication and in the proofreading necessary for repair of DNA damage (summary by Frugoni et al., 2016).
Purified human HeLa POLE consists of a 261-kD catalytic subunit (174762) and a 55-kD accessory subunit. Li et al. (1997) cloned the small subunit of human POLE, which they symbolized DPE2. The cDNA predicted a 526-amino acid protein. The gene product has 26% identity to DPB2, a POLE accessory protein in the yeast S. cerevisiae.
Li et al. (1997) assigned the DPE2 gene to human chromosome 14 using human-rodent hybrid panels. The gene was then regionally localized to 14q13-q21 by fluorescence in situ hybridization.
Stumpf (2021) mapped the POLE2 gene to chromosome 14q21.3 based on an alignment of the POLE2 sequence (GenBank BC112962) with the genomic sequence (GRCh38).
Associations Pending Confirmation
For discussion of a possible association between a primary immunodeficiency and variation in the POLE2 gene, see 602670.0001.
This variant is classified as a variant of unknown significance because its contribution to a primary immunodeficiency has not been confirmed.
In a boy, born of consanguineous Saudi parents, with a primary combined immunodeficiency, Frugoni et al. (2016) identified a homozygous G-to-T transversion in intron 13 of the POLE2 gene, resulting in a splicing abnormality. RT-PCR analysis of patient cells showed 2 transcripts: 1 with an in-frame deletion of 3 bp, predicted to result in the deletion of conserved residue ser359, and a shorter transcript with skipping of exon 14. Immunoblot analysis showed normal expression of the POLE2 protein. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP or 1000 Genomes Project databases. Patient PBMCs and fibroblasts showed failed DNA replication in the S phase with an increased proportion of cells in the G2/M phase compared to controls. Expression of wildtype POLE2 partially rescued the defects in cell cycle progression. The authors suggested that the variant caused a defect in accurate DNA repair during proliferative bursts associated with antigen receptor rearrangement in stimulated immune cells. The patient had a history of multiple recurrent infections since infancy, including systemic BCG infection after immunization. Diabetes mellitus and hypothyroidism were also diagnosed in infancy. Laboratory studies showed agammaglobulinemia, absence of circulating B cells, T-cell lymphopenia, neutropenia, lack of T-cell receptor excision circles (TRECs), and decreased NK cells. Further detailed studies showed a severe block in B-cell development and an abrogated response to antigens. He had poor overall growth and dysmorphic features, including low anterior hairline, flat supraorbital ridges, downturned corners of the mouth, and short philtrum. The patient developed hemophagocytic lymphohistiocytosis and died at age 7 years, 11 months.
Frugoni, F., Dobbs, K., Felgentreff, K., Aldhekri, H., Al Saud, B. K., Arnaout, R., Ali, A. A., Abhyankar, A., Alroqi, F., Giliani, S., Ojeda, M. M., Tsitsikov, E., Pai, S.-Y., Casanova, J. L., Notarangelo, L. D., Manis, J. P. A novel mutation in the POLE2 gene causing combined immunodeficiency. J. Allergy Clin. Immun. 137: 635-638, 2016. [PubMed: 26365386] [Full Text: https://doi.org/10.1016/j.jaci.2015.06.049]
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]
Stumpf, A. M. Personal Communication. Baltimore, Md. 03/26/2021.