Alternative titles; symbols
HGNC Approved Gene Symbol: POLA1
SNOMEDCT: 717224002, 718914002;
Cytogenetic location: Xp22.11-p21.3 Genomic coordinates (GRCh38): X:24,693,918-24,996,986 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.11-p21.3 | Pigmentary disorder, reticulate, with systemic manifestations, X-linked | 301220 | X-linked recessive | 3 |
| Van Esch-O'Driscoll syndrome | 301030 | X-linked recessive | 3 |
The POLA1 gene encodes the catalytic subunit of DNA polymerase-alpha, which is an essential component of DNA replication machinery. The POLA complex synthesizes RNA:DNA primers which initiate the synthesis of Okazaki fragments (summary by Starokadomskyy et al., 2016).
Van Esch et al. (2019) assessed Pola1 expression by in situ hybridization in the embryonic and adult mouse brain, and observed expression in zones of the forebrain containing proliferating cells in the developing embryonic neocortex, as well as in the lateral and medial ganglionic eminences. At 3 weeks after birth, Pola1 was expressed in cells that remain proliferating in the ventricular and subventricular zones of the striatum, suggesting that Pola1 has a role in neurogenesis throughout life.
Hanaoka et al. (1985) complemented a temperature-sensitive defect in murine POLA by fusing the defective mouse cells with human cells. A gene present on Xpter-q22 was responsible for correcting the defect. The temperature-sensitive mutant used by Hanaoka et al. (1985) was derived from mouse FM3A cells (tsFT20, hprt-negative). Other temperature-sensitive mutations of hamster and mouse are corrected by the long arm (q13-q27) of the human X chromosome (see 313650). Wang et al. (1985) used a monoclonal antibody that distinguishes human from rodent DNA polymerase alpha to study human-rodent cell hybrids. They mapped the gene to a site near the junction of Xp21.3 and Xp22.1 (perhaps Xp21.12-p21.11) and showed that it is not expressed in an inactive X chromosome. They concluded that POLA is distal to DMD (300377) and CGD (306400) but proximal to STS (300747). They predicted that mosaic nullisomy in a female resulting from deletion of this gene could not exist and that hemizygosity for deletion of the gene in a male would be lethal because of the essentiality of the gene to the catalytic activity of DNA polymerase alpha. Miyazawa et al. (1986) showed that the human DNA polymerase alpha gene is located in a DNA segment of 400-500 kb. By in situ hybridization, Adler et al. (1991) mapped the Pola gene to the mouse X chromosome in region C-D.
Starokadomskyy et al. (2016) found that cytosolic POLA1 colocalized with RNA:DNA in a speckled pattern; this interaction was dependent upon POLA1 polymerase activity.
Reticulate Pigmentary Disorder with Systemic Manifestations, X-Linked
In affected members of 12 unrelated families with X-linked reticulate pigmentary disorder (PDR; 301220), Starokadomskyy et al. (2016) identified a hemizygous (in males) or heterozygous (in females) intronic mutation in the POLA1 gene (312040.0001). All affected individuals carried the same mutation, which was initially identified by whole-genome sequencing of 4 probands. Haplotype analysis showed that 2 of the families shared a common founder, but others gained the mutation independently, including at least 1 de novo case. Cells derived from patients with the mutation showed increased expression of genes involved in type I interferon (see IFNA1, 147660) signaling pathways and other proinflammatory genes. Patient cells showed enhanced activation of genes in the interferon regulatory factor (IRF; see 147575) and NFKB (see 164011) pathways in response to double-stranded DNA, cytosolic double-stranded RNA, and TNF (191160). Patient cells also showed almost undetectable cytosolic RNA:DNA, which was rescued by expression of wildtype POLA1. Transfection of endogenous and synthesized RNA:DNA into POLA1-deficient cells normalized the increased expression of IRF genes. The findings suggested that the splice site mutation caused POLA1 deficiency, which resulted in constitutive activation of IRF- and NFKB-dependent genes and an increased type I interferon profile, possibly by the reduction in the POLA1-mediated generation of cytosolic RNA:DNA. Starokadomskyy et al. (2016) noted that RNA:DNA hybrids may function to squelch an inflammatory response generated by stimulatory nucleic acids.
Van Esch-O'Driscoll Syndrome
In 9 affected male patients from 5 unrelated families with developmental delay/intellectual disability, growth failure, microcephaly, and hypergonadotropic hypogonadism (VEODS; 301030), Van Esch et al. (2019) identified 5 different mutations in the POLA1 gene. Carrier females were unaffected, and all showed significant to complete skewing of X-inactivation. Findings in patient cells were consistent with spontaneously diminished productive replication initiation under unperturbed exponential growth conditions.
Among eutherian (inaccurately called 'placental') mammals, not a single exception has been found to Ohno's law of the evolutionary conservation of the genic content of the X chromosome; however, Watson et al. (1991) found exceptions in the case of marsupial and monotreme mammals. Marsupials (mammalian infraclass Metatheria) diverged from eutherians 120-150 million years ago; monotremes (subclass Prototheria) diverged from the therian (eutherian and metatherian) lineage 150-170 million years ago. Whereas genes on the long arm of the human X chromosome are found to be conserved on the X chromosomes of all mammals including marsupials and monotremes, Watson et al. (1991), using in situ hybridization, demonstrated that 5 human Xp genes (POLA, DMD, SYN1, CYBB, MAOA) are located in 2 clusters on autosomes in marsupials as well as in the platypus (a monotreme). They suggested that the human Xp region was originally autosomal and was translocated to the sex chromosomes in the eutherian lineage.
In affected members of 12 unrelated families with X-linked reticulate pigmentary disorder (PDR; 301220), Starokadomskyy et al. (2016) identified a g.24744696A-G transition (g.24744696A-G, NC_000023.10) in intron 13 of the POLA1 gene, resulting the introduction of a novel exon (exon 13a) into the transcript. All affected individuals carried the same mutation, which was initially identified by whole-genome sequencing of 4 probands. The variant was filtered against the 1000 Genomes Project and 18 male controls; it was not found in 1,133 control genomes. The mutation segregated with the disorder in 5 multiplex families tested. Patient fibroblasts and lymphoblastoid cells showed aberrant splicing and a decrease in POLA1 protein levels to about 35% that of controls. However, no truncated protein was detected and patient cells did not show abnormalities in proliferation or cell replication. These findings suggested that the mutation resulted in a hypomorphic POLA1 allele.
In 4 affected male individuals from a 5-generation Belgian family (family A) with developmental delay/intellectual disability, growth failure, microcephaly, and hypergonadotropic hypogonadism (VEODS; 301030), Van Esch et al. (2019) identified a c.236T-G transversion (c.236T-G, NM_016937.3) in exon 3 of the POLA1 gene, resulting in an ile79-to-ser (I79S) substitution at a highly conserved residue. The mutation segregated fully in affected individuals and carrier mothers, and was not found in the dbSNP, 1000 Genomes Project, ExAC, or gnomAD databases. Carrier females showed significant skewing of X inactivation. Under conditions of stress, patient lymphoblastoid cell lines (LCLs) exhibited significantly reduced EdU incorporation compared to control LCLs, indicative of impaired DNA replication.
In a 16-year-old boy (family B) with developmental delay/intellectual disability, growth failure, microcephaly, and hypergonadotropic hypogonadism (VEODS; 301030), Van Esch et al. (2019) identified a c.4142C-T transition (c.4142C-T, NM_016937.3) in the POLA1 gene, resulting in a pro1381-to-leu (P1381L) substitution at a conserved residue. His unaffected sister, mother, and maternal grandmother carried the mutation, which was not found in the dbSNP, 1000 Genomes Project, ExAC, or gnomAD databases. Carrier females showed significant skewing of X inactivation. Under conditions of stress, patient lymphoblastoid cell lines (LCLs) exhibited significantly reduced EdU incorporation compared to control LCLs, indicative of impaired DNA replication.
In a 5-year-old boy and his male cousin (family C) who died at age 14 months with developmental delay/intellectual disability, growth failure, microcephaly, and hypergonadotropic hypogonadism (VEODS; 301030), Van Esch et al. (2019) identified a splicing mutation (c.507+1G-A, NM_016937.3) in intron 6 of the POLA1 gene, predicted to abolish the donor splice site. RNA analysis showed that the mutation prevents normal splicing and results in production of 2 abnormal transcripts: one due to use of a cryptic splice donor site within intron 6 which inserts the first 60 nucleotides of the intron, causing a frameshift resulting in a premature termination codon (Thr170_Ser1462delinsTer15), and the other resulting from exon 6 skipping and an in-frame deletion (Lys149_Glu169del). Both unaffected mothers and the maternal grandmother carried the mutation, which was not found in the dbSNP, 1000 Genomes Project, ExAC, or gnomAD databases. Carrier females showed significant to complete skewing of X inactivation. Whole-cell extracts from patient cells showed a marked reduction in POLA1 protein levels; chromatin extracts showed a 60% reduction compared to wildtype. Analysis of DNA replication capacity in lymphoblastoid cell lines (LCLs) from the proband demonstrated a reduction in new initiation events, increased interorigin distance, an increase in asymmetric forks, and an accumulation of longer replication tracts compared to LCLs from his father. Under conditions of stress, there was an approximately 2-fold increase in stalled replication forks in combed fibers from proband LCLs, with significantly less incorporation of EdU, compared to paternal LCLs.
In a 7-year-old boy (family D) with developmental delay/intellectual disability, growth failure, microcephaly, and hypergonadotropic hypogonadism (VEODS; 301030), Van Esch et al. (2019) identified a de novo in-frame deletion (c.445_507del, NM_016937.3) of exon 6 of the POLA1 gene, producing a protein lacking 21 amino acids (Lys149_Glu169del). The mutation was not found in the dbSNP, 1000 Genomes Project, ExAC, or gnomAD databases.
In a 4.5-year-old boy (family E) with developmental delay/intellectual disability, growth failure, microcephaly, and hypergonadotropic hypogonadism (VEODS; 301030), Van Esch et al. (2019) identified a de novo c.328G-A transition (c.328G-A, NM_016937.3) at the last nucleotide in exon 4 of the POLA1 gene, resulting in a gly110-to-arg (G110R) substitution predicted to disrupt splicing. The mutation was not found in the dbSNP, 1000 Genomes Project, ExAC, or gnomAD databases. Analysis of patient cells revealed a marked reduction of POLA1 mRNA and protein levels compared to control cells.
Adler, D. A., Tseng, B. Y., Wang, T. S.-F., Disteche, C. M. Physical mapping of the genes for three components of the mouse DNA replication complex: polymerase alpha to the X chromosome, primase p49 subunit to chromosome 10, and primase p58 subunit to chromosome 1. Genomics 9: 642-646, 1991. [PubMed: 2037291] [Full Text: https://doi.org/10.1016/0888-7543(91)90357-k]
Hanaoka, F., Tandai, M., Miyazawa, H., Murakami, Y., Hori, T., Yamada, M. Assignment of human DNA polymerase alpha gene (POLA) to the X chromosome. (Abstract) Cytogenet. Cell Genet. 40: 647 only, 1985.
Miyazawa, H., Tandai, M., Hanaoka, F., Yamada, M., Hori, T., Shimizu, K., Sekiguchi, M. Identification of a DNA segment containing the human DNA polymerase alpha gene. Biochem. Biophys. Res. Commun. 139: 637-643, 1986. [PubMed: 3767982] [Full Text: https://doi.org/10.1016/s0006-291x(86)80038-9]
Starokadomskyy, P., Gemelli, T., Rios, J. J., Xing, C., Wang, R. C., Li, H., Pokatayev, V., Dozmorov, I., Khan, S., Miyata, N., Fraile, G., Raj, P., and 19 others. DNA polymerase-alpha regulates the activation of type I interferons through cytosolic RNA:DNA synthesis. Nature Immun. 17: 495-504, 2016. [PubMed: 27019227] [Full Text: https://doi.org/10.1038/ni.3409]
Van Esch, H., Colnaghi, R., Freson, K., Starokadomskyy, P., Zankl, A., Backx, L., Abramowicz, I., Outwin, E., Rohena, L., Faulkner, C., Leong, G. M., Newbury-Ecob, R. A., Challis, R. C., Ounap, K., Jaeken, J., Seuntjens, E., Devriendt, K., Burstein, E., Low, K. J., O'Driscoll, M. Defective DNA polymerase alpha-primase leads to X-linked intellectual disability associated with severe growth retardation, microcephaly, and hypogonadism. Am. J. Hum. Genet. 104: 957-967, 2019. [PubMed: 31006512] [Full Text: https://doi.org/10.1016/j.ajhg.2019.03.006]
Wang, T. S.-F., Pearson, B. E., Suomalainen, H. A., Mohandas, T., Shapiro, L. J., Schroder, J., Korn, D. Assignment of the gene for human DNA polymerase alpha to the X chromosome. Proc. Nat. Acad. Sci. 82: 5270-5274, 1985. [PubMed: 2410918] [Full Text: https://doi.org/10.1073/pnas.82.16.5270]
Watson, J. M., Spencer, J. A., Riggs, A. D., Graves, J. A. M. Sex chromosome evolution: platypus gene mapping suggests that part of the human X chromosome was originally autosomal. Proc. Nat. Acad. Sci. 88: 11256-11260, 1991. [PubMed: 1763040] [Full Text: https://doi.org/10.1073/pnas.88.24.11256]