Alternative titles; symbols
HGNC Approved Gene Symbol: POLR3K
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:46,407-53,608 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Leukodystrophy, hypomyelinating, 21 | 619310 | Autosomal recessive | 3 |
Transcription in eukaryotic cells involves 3 distinct RNA polymerases, pol I, pol II, and pol III (see POLR2A; 180660). Pol III transcribes significantly shorter genes than those transcribed by pol I and pol II. In the absence of proteins such as TFIIS (TCEA1; 601425) and TFIIF (GTF2F1; 189968), RNA polymerases are prevented from completing transcription, a phenomenon known as transcription arrest. POLR3K is a TFIIS-like RNA pol III subunit that is essential for cell viability and is required for the intrinsic 3-prime exonucleolytic cleavage activity of pol III ternary complexes (Chedin et al., 1998).
By searching a database for sequences similar to yeast C11, Chedin et al. (1998) obtained a cDNA encoding human POLR3K, which they called C11. The deduced 108-amino acid protein contains N- and C-terminal zinc-binding motifs and an intermediate domain with a conserved 9-residue sequence (KEVDDVLGG). Each domain is encoded by a separate exon in the human gene. The C-terminal zinc-binding motif is 67% similar to the zinc ribbon of TFIIS. Functional analysis in yeast showed that C11 is involved in both the cleavage activity of nascent transcripts in arrested Pol III transcription complexes, like TFIIS, and in their transition to the elongation state. Spakovskii and Lebedenko (1998) also cloned and characterized POLR3K.
By genomic sequence analysis, Chedin et al. (1998) determined that the POLR3K gene contains 3 exons and spans over 7 kb.
Chedin et al. (1998) mapped the POLR3K gene to chromosome 16 by genomic sequence analysis.
Stumpf (2021) mapped the POLR3K gene to chromosome 16p13.3 based on an alignment of the POLR3K sequence (GenBank BC011932) with the genomic sequence (GRCh38).
In 2 unrelated boys, each born of consanguineous parents of Berber origin in Algeria, with hypomyelinating leukodystrophy-21 (HLD21; 619310), Dorboz et al. (2018) identified a homozygous missense mutation in the POLR3K gene (R41W; 606007.0001). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. It was not found in several public databases, including gnomAD, or in 500 ethnically-matched control chromosomes. Patient fibroblasts showed reduced expression of tRNA(imet), 5S rRNA (see 180420), and 7SL RNA (see 612177) compared to controls. The findings suggested that disrupted RNA regulation resulting from the mutation contributed to the neurologic dysfunction observed in these patients.
In 2 unrelated boys, each born of consanguineous parents of Berber origin in Algeria, with hypomyelinating leukodystrophy-21 (HLD21; 619310), Dorboz et al. (2018) identified a homozygous c.121C-T transition (c.121C-T, NM_016310.4) in the POLR3K gene, resulting in an arg41-to-trp (R41W) substitution in the highly conserved domain II of the protein. The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. It was not found in several public databases, including gnomAD, or in 500 ethnically-matched control chromosomes. Patient fibroblasts showed reduced expression of tRNA(imet), 5S rRNA (see 180420), and 7SL RNA (see 612177) compared to controls. The findings suggested that disrupted RNA regulation resulting from the mutation contributed to the neurologic dysfunction observed in these patients.
Chedin, S., Riva, M., Schultz, P., Sentenac, A., Carles, C. The RNA cleavage activity of RNA polymerase III is mediated by an essential TFIIS-like subunit and is important for transcription termination. Genes Dev. 12: 3857-3871, 1998. [PubMed: 9869639] [Full Text: https://doi.org/10.1101/gad.12.24.3857]
Dorboz, I., Dumay-Odelot, H., Boussaid, K., Bouyacoub, Y., Barreau, P., Samaan, S., Jmel, H., Eymard-Pierre, E., Cances, C., Bar, C., Poulat, A.-L., Rousselle, C., Renaldo, F., Elmaleh-Berges, M., Teichmann, M., Boespflug-Tanguy, O. Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation. Neurol. Genet. 4: e289, 2018. [PubMed: 30584594] [Full Text: https://doi.org/10.1212/NXG.0000000000000289]
Spakovskii, G. V., Lebedenko, E. N. Molecular identification and characteristics of hRPC11, the smallest specific subunit of human RNA polymerase III. Bioorg. Khim. 24: 877-880, 1998. [PubMed: 10079944]
Stumpf, A. M. Personal Communication. Baltimore, Md. 05/04/2021.