Alternative titles; symbols
HGNC Approved Gene Symbol: POLR1C
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38): 6:43,517,089-44,461,400 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.1 | Leukodystrophy, hypomyelinating, 11 | 616494 | Autosomal recessive | 3 |
| Treacher Collins syndrome 3 | 248390 | Autosomal recessive | 3 |
The POLR1C gene encodes a subunit that is shared by both RNA polymerase I (POLR1) and RNA polymerase III (POLR3) (summary by Thiffault et al., 2015).
By sequencing cDNAs obtained from umbilical cord blood CD34 (142230)-positive hematopoietic stem/progenitor cells, Mao et al. (1998) cloned POLR1C, which they called RPA40. The deduced protein contains 342 amino acids.
By sequencing proteins contained within RNA polymerase III complexes purified from HeLa cells, followed by database analysis, Hu et al. (2002) identified POLR1C, which they called RPAC1. The deduced 342-amino acid protein has a calculated molecular mass of 38.6 kD and shares 47% amino acid identity with its yeast homolog, AC40.
Stumpf (2022) mapped the POLR1C gene to chromosome 6p21.1 based on an alignment of the POLR1C sequence (GenBank BC008863) with the genomic sequence (GRCh38).
Treacher Collins Syndrome 3
Dauwerse et al. (2011) analyzed the POLR1C gene in 252 individuals with Treacher Collins syndrome (TCS3; 248390) and identified 3 patients with compound heterozygous mutations (610060.0001-610060.0005).
Hypomyelinating Leukodystrophy 11
In 8 patients with hypomyelinating leukodystrophy-11 (HLD11; 616494) who were negative for mutations in the POLR3A (614258) and POLR3B (614366) genes, Thiffault et al. (2015) identified 13 homozygous or compound heterozygous mutations in the POLR1C gene (see, e.g., 610060.0006-610060.0011). Mutations in the first 3 patients were found by whole-exome sequencing and segregated with the disorder in the families. Subsequent mutations in 5 patients were found by direct sequencing of the POLR1C gene in 16 individuals with a similar phenotype who were negative for POLR3A and POLR3B mutations.
In in vitro functional expression assays in HeLa cells, Thiffault et al. (2015) found that the POLR1C R279Q mutation (610060.0001) associated with Treacher Collins syndrome did not affect the assembly of either RNA polymerase I or III. However, the R279Q mutation impaired targeting of the protein to the nucleolus, the site for RNA polymerase I gene transcription. In contrast, 2 missense mutations associated with HLD11 (N74S; 610060.0006 and N32I; 610060.0007) specifically interfered with assembly and nuclear import of RNA polymerase III, but not RNA polymerase I. The findings provided a pathophysiologic mechanism for the different clinical conditions resulting from different mutations in the same gene.
In a sister and brother and an unrelated male patient with Treacher Collins syndrome-3 (TCS3; 248390), Dauwerse et al. (2011) identified compound heterozygosity for an 836G-A transition in exon 8 of the POLR1C gene, resulting in an arg279-to-gln (R279Q) substitution at a highly conserved residue in the RNA polymerase dimerization domain of POLR1C, and another mutation in POLR1C. The second mutation in the sister and her more severely affected brother, who had previously been studied by Splendore et al. (2000), was a 4-bp deletion in intron 8 (610060.0002) at the splice donor site (922+3_922+6del), predicted to result in skipping of exon 8. The unrelated patient's second mutation was a 979A-T transversion in exon 9, resulting in a lys327-to-ter (K327X; 610060.0003) substitution. The unrelated patient's unaffected parents were each heterozygous for 1 of the mutations; the sibs' unaffected mother and her healthy sister were heterozygous for the R279Q mutation, but DNA from their deceased father was unavailable for study.
For discussion of the 4-bp deletion in the POLR1C gene (922+3_922+6del) that was found in compound heterozygous state in sibs with Treacher Collins syndrome-3 (TCS3; 248390) by Dauwerse et al. (2011), see 610060.0001.
For discussion of the lys327-to-ter (K327X) mutation in the POLR1C gene that was found in compound heterozygous state in a patient with Treacher Collins syndrome-3 (TCS3; 248390) by Dauwerse et al. (2011), see 610060.0001.
In a male patient with Treacher Collins syndrome-3 (TCS3; 248390), Dauwerse et al. (2011) identified compound heterozygosity for 2 mutations in the POLR1C gene: a 1-bp deletion (87delT) in exon 2, predicted to cause a frameshift and a premature termination codon, and an 835C-T transition in exon 8, resulting in an arg279-to-trp (R279W) substitution (610060.0005). His unaffected parents were each heterozygous for 1 of the mutations.
For discussion of the arg279-to-trp (R279W) mutation in the POLR1C gene that was found in compound heterozygous state in a patient with Treacher Collins syndrome-3 (TCS3; 248390) by Dauwerse et al. (2011), see 610060.0004.
In a Hungarian boy with hypomyelinating leukodystrophy-11 (HLD11; 616494), Thiffault et al. (2015) identified a homozygous c.221A-G transition (c.221A-G, NM_203290) in exon 3 of the POLR1C gene, resulting in an asn74-to-ser (N74S) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at a very low frequency (less than 0.01%) in the Exome Sequencing Project and ExAC databases and was not found in the CEPH database. In vitro functional expression studies in HeLa cells showed that the mutant protein interacted less well with POLR3 than did wildtype, suggesting a selective defect in POLR3 assembly that did not affect POLR1 assembly. Immunofluorescence and immunoprecipitation studies showed cytoplasmic accumulation of mutated POLR1C subunits and reduced binding to POLR3-transcribed genes. In contrast, there was no difference between mutant and wildtype POLR1C in binding to POLR1-transcribed genes. The findings indicated that the N74S mutation specifically interfered with assembly, nuclear import, and chromatin association of POLR3.
In a boy, born of consanguineous Libyan parents, with hypomyelinating leukodystrophy-11 (HLD11; 616494), Thiffault et al. (2015) identified a homozygous c.95A-T transversion (c.95A-T, NM_203290) in exon 2 of the POLR1C gene, resulting in an asn32-to-ile (N32I) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the Exome Sequencing Project, ExAC, or CEPH databases. In vitro functional expression studies in HeLa cells showed that the mutant protein interacted less well with POLR3 than did wildtype, suggesting a selective defect in POLR3 assembly that did not affect POLR1 assembly. Immunofluorescence and immunoprecipitation studies showed cytoplasmic accumulation of mutated POLR1C subunits and reduced binding to POLR3-transcribed genes. In contrast, there was no difference between mutant and wildtype POLR1C in binding to POLR1-transcribed genes. The findings indicated that the N32I mutation specifically interfered with assembly, nuclear import, and chromatin association of POLR3.
In a Chinese boy with hypomyelinating leukodystrophy-11 (HLD11; 616494), Thiffault et al. (2015) identified compound heterozygous mutations in the POLR1C gene: a c.436T-C transition (c.436T-C, NM_203290) in exon 5, resulting in a cys146-to-arg (C146R) substitution at a highly conserved residue, and a 3-bp deletion in exon 8 (c.883_885delAAG; 610060.0009), resulting in an in-frame deletion of a conserved residue (Lys295del). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the Exome Sequencing Project, ExAC, or CEPH databases. Functional studies of the variants were not performed.
For discussion of the c.883_885delAAG (c.883_885delAAG, NM_203290) mutation in the POLR1C gene that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-11 (HLD11; 616494) by Thiffault et al. (2015), see 610060.0008.
In a girl with hypomyelinating leukodystrophy-11 (HLD11; 616494), Thiffault et al. (2015) identified compound heterozygous mutations in the POLR1C gene: a c.77C-T transition (c.77C-T, NM_203290) in exon 2, resulting in a thr26-to-ile (T26I) substitution, and a c.326G-A transition in exon 4, resulting in an arg109-to-his (R109H; 610060.0011) substitution. Each unaffected parent was heterozygous for 1 of the mutations. Both mutations occurred at conserved residues. The variants were not found in the Exome Variant Server, Exome Aggregation Consortium, or CEPH databases, and functional studies were not performed.
For discussion of the c.326G-A transition (c.326G-A, NM_203290) in the POLR1C gene, resulting in an arg109-to-his (R109H) substitution, that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-11 (HLD11; 616494) by Thiffault et al. (2015), see 610060.0010.
Dauwerse, J. G., Dixon, J., Seland, S., Ruivenkamp, C. A. L., van Haeringen, A., Hoefsloot, L. H., Peters, D. J. M., Clement-de Boers, A., Daumer-Haas, C., Maiwald, R., Zweier, C., Kerr, B., Cobo, A. M., Toral, J. F., Hoogeboom, A. J. M., Lohmann, D. R., Hehr, U., Dixon, M. J., Breuning, M. H., Wieczorek, D. Mutations in gene encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nature Genet. 43: 20-22, 2011. [PubMed: 21131976] [Full Text: https://doi.org/10.1038/ng.724]
Hu, P., Wu, S., Sun, Y., Yuan, C.-C., Kobayashi, R., Myers, M. P., Hernandez, N. Characterization of human RNA polymerase III identifies orthologues for Saccharomyces cerevisiae RNA polymerase III subunits. Molec. Cell. Biol. 22: 8044-8055, 2002. [PubMed: 12391170] [Full Text: https://doi.org/10.1128/MCB.22.22.8044-8055.2002]
Mao, M., Fu, G., Wu, J.-S., Zhang, Q.-H., Zhou, J., Kan, L.-X., Huang, Q.-H., He, K.-L., Gu, B.-W., Han, Z.-G., Shen, Y., Gu, J., Yu, Y.-P., Xu, S.-H., Wang, Y.-X., Chen, S.-J., Chen, Z. Identification of genes expressed in human CD34+ hematopoietic stem/progenitor cells by expressed sequence tags and efficient full-length cDNA cloning. Proc. Nat. Acad. Sci. 95: 8175-8180, 1998. [PubMed: 9653160] [Full Text: https://doi.org/10.1073/pnas.95.14.8175]
Splendore, A., Silva, E. O., Alonso, L. G., Richieri-Costa, A., Alonso, N., Rosa, A., Carakushanky, G., Cavalcanti, D. P., Brunoni, D., Passos-Bueno, M. R. High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes. Hum. Mutat. 16: 315-322, 2000. [PubMed: 11013442] [Full Text: https://doi.org/10.1002/1098-1004(200010)16:4<315::AID-HUMU4>3.0.CO;2-H]
Stumpf, A. M. Personal Communication. Baltimore, Md. 02/21/2022.
Thiffault, I., Wolf, N. I., Forget, D., Guerrero, K., Tran, L. T., Choquet, K., Lavallee-Adam, M., Poitras, C., Brais, B., Yoon, G., Sztriha, L., Webster, R. I., and 15 others. Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III. Nature Commun. 6: 7623, 2015. Note: Electronic Article. [PubMed: 26151409] [Full Text: https://doi.org/10.1038/ncomms8623]