Alternative titles; symbols
HGNC Approved Gene Symbol: POLR3E
Cytogenetic location: 16p12.2 Genomic coordinates (GRCh38): 16:22,297,409-22,335,096 (from NCBI)
The POLR3E gene encodes a subunit of RNA polymerase III, which primarily transcribes small noncoding RNAs, such as rRNA and tRNA. Pol III also has a noncanonical role of viral DNA sensing in the innate immune system in which it transcribes viral genomes to produce RNAs that lead to induction of a type I interferon response (summary by Ramanathan et al., 2020).
By searching an EST database for sequences similar to Drosophila 'sex-lethal interactor' (sin), Dong and Bell (1999) identified mouse and human POLR3E, which they called SIN.
By sequencing clones obtained from a size-fractionated human fetal brain cDNA library, Nagase et al. (2000) cloned POLR3E, which they designated KIAA1452. The transcript contains several repetitive elements in its 3-prime end, and the deduced protein contains 694 amino acids. RT-PCR ELISA detected variable KIAA1452 expression in all adult and fetal tissues examined, with highest expression in ovary, followed by testis and kidney. KIAA1452 was also expressed in all specific adult brain regions examined.
By yeast 2-hybrid analysis and protein pull-down assays, Dong and Bell (1999) found that Drosophila sin interacted with the pre-mRNA splicing regulator 'sex lethal' (sxl). The interaction was resistant to RNase treatment, suggesting that the association was not mediated by RNA.
By PCR of a radiation hybrid panel, Nagase et al. (2000) mapped the POLR3E gene to chromosome 16.
Hartz (2017) mapped the POLR3E gene to chromosome 16p12.2 based on an alignment of the POLR3E sequence (GenBank AK001371) with the genomic sequence (GRCh38).
Associations Pending Confirmation
For discussion of a possible association between a primary immunodeficiency with increased susceptibility to viral infections and variation in the POLR3E gene, see 617815.0001.
This variant is classified as a variant of unknown significance because its contribution to an immunodeficiency with susceptibility to viral infections has not been confirmed.
In a 12-month-old girl, born of consanguineous parents, with a virus-specific immunodeficiency, Ramanathan et al. (2020) identified a homozygous variant (chr16.22,319,499G-C, GRCh37) in the POLR3E gene, resulting in an asp40-to-his (D40H) substitution. The variant, which was found by whole-exome sequencing, segregated with the disorder in the family. It was found once in the homozygous state in the gnomAD database, and in the heterozygous state in 49 of 138,089 individuals. When subjected to CMV infection in vitro, patient fibroblasts showed increased susceptibility to this specific infection and had an impaired type I interferon response compared to controls. Studies in wildtype retinal pigment epithelial cells showed that both DNA and RNA viruses induced POLR3E expression and transcriptional activity. Transfection of the D40H variant into HEK293 cells showed that it inhibited activation of POLR3E transcription due to defective assembly and function of the initiation complex. Coexpression of the variant with wildtype POLR3E did not rescue the defects, suggesting a possible dominant-negative effect. The patient had multiple viral infections beginning in infancy, including CMV, RSV, parvovirus, parainfluenza 3, and HHV6. She also developed Langerhans cell histiocytosis, which the authors suggested may have been due to persistent activation of dendritic cells in response to recurrent viral infections in the context of innate immunodeficiency.
Dong, Z., Bell, L. R. SIN, a novel Drosophila protein that associates with the RNA binding protein sex-lethal. Gene 237: 421-428, 1999. [PubMed: 10521666] [Full Text: https://doi.org/10.1016/s0378-1119(99)00303-0]
Hartz, P. A. Personal Communication. Baltimore, Md. 12/18/2017.
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 143-150, 2000. [PubMed: 10819331] [Full Text: https://doi.org/10.1093/dnares/7.2.143]
Ramanathan, A., Weintraub, M., Orlovetskie, N., Serruya, R., Mani, D., Marcu, O., Stepensky, P., Weisblum, Y., Djian, E., Shaag, A., Revel-Vilk, S., Fried, I., Kotler, M., Rouvinski, A., Wolf, D., Elpeleg, O., Jarrous, N. A mutation in POLR3E impairs antiviral immune response and RNA polymerase III. Proc. Nat. Acad. Sci. 117: 22113-22121, 2020. [PubMed: 32843346] [Full Text: https://doi.org/10.1073/pnas.2009947117]