Alternative titles; symbols
HGNC Approved Gene Symbol: POLR1B
Cytogenetic location: 2q14.1 Genomic coordinates (GRCh38) : 2:112,542,036-112,579,818 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q14.1 | Treacher-Collins syndrome 4 | 618939 | Autosomal dominant | 3 |
Eukaryotic RNA polymerase I (pol I) is responsible for the transcription of ribosomal RNA (rRNA) genes and production of rRNA, the primary component of ribosomes. Pol I is a multisubunit enzyme composed of 6 to 14 polypeptides, depending on the species. Most of the mass of the pol I complex derives from the 2 largest subunits, Rpa1 and Rpa2 in yeast. POLR1B is homologous to Rpa2 (Seither and Grummt, 1996).
Seither and Grummt (1996) cloned a mouse cDNA encoding Rpa2, the second largest pol I subunit. The 3,978-bp open reading frame encodes a 1,136-amino acid polypeptide with a calculated molecular mass of 128 kD. Sequence alignment with the corresponding Drosophila and yeast genes revealed the same level of sequence similarity among Rpa2 genes as exists for Rpa1 genes across diverse species.
By in situ hybridization, Sanchez et al. (2020) analyzed polr1b expression during zebrafish embryogenesis and observed that although polr1b was ubiquitously expressed during gastrulation from 50% epiboly to bud stages, its expression became spatially restricted during segmentation in the retina, tectum, and somite. The tissue restriction of polr1b expression continued during pharyngula to become specific to the eye, tectum, posterior myotomes, and branchial arches.
Stumpf (2020) mapped the POLR1B gene to chromosome 2q14.1 based on an alignment of the POLR1B sequence (GenBank BC110833) with the genomic sequence (GRCh38).
In 6 female patients from 5 families with Treacher Collins syndrome (TCS4; 618939), Sanchez et al. (2020) identified heterozygosity for 3 different missense mutations in the POLR1B gene: R1003C (602000.0001) in 3 patients, R1003S (602000.0002) in 1 patient, and S682R (602000.0003) in an affected mother and daughter.
Sanchez et al. (2020) observed that morpholino knockdown of polr1b in zebrafish embryos resulted in abnormal craniofacial development at 20 hours postfertilization (hpf), characterized by cranioskeletal hypoplasia, microtia, and microphthalmia. In addition, 72-hpf polr1b morphants were proportionally smaller and exhibited cardiac edema, altered positioning of melanocytes along the anterior-posterior axis, and pectoral fin hypoplasia compared to controls. Analysis of neural crest cell (NCC) development and behavior showed that the smaller head observed in polr1b morphants was associated with decreased numbers of migrating NCCs positive for sox10 (602229) or foxd3 (611539) in the head, particularly where branchial arches normally formed. At 3 days postfertilization, the polr1b morphants lacked mandibular and branchial arches, and the otic vesicle was smaller and misshapen, compared to control morphants. The authors noted that the morphants showed phenotypic similarities to patients with POLR1B-associated Treacher Collins syndrome (see TCS4, 618939 and MOLECULAR GENETICS), and that the zebrafish phenotype was associated with altered ribosomal gene expression, massive p53 (191170)-associated cellular apoptosis in the neuroepithelium, and reduced numbers of NCC derivatives.
In 3 unrelated girls (patients 1, 4, and 6) with Treacher Collins syndrome (TCS4; 618939), Sanchez et al. (2020) identified heterozygosity for a de novo c.3007C-T transition (c.3007C-T, NM_019014.5) in exon 15 of the POLR1B gene, resulting in an arg1003-to-cys (R1003C) substitution at a highly conserved residue located in a hydrogen bond that participates in stabilization of the alpha-helix.
In a 20-year-old woman (patient 5) with Treacher Collins syndrome (TCS4; 618939), Sanchez et al. (2020) identified heterozygosity for a c.3007C-A transversion (c.3007C-A, NM_019014.5) in exon 15 of the POLR1B gene, resulting in an arg1003-to-ser (R1003S) substitution at a highly conserved residue located in a hydrogen bond that participates in stabilization of the alpha-helix. Analysis of parental DNA revealed mosaicism in samples from her father, with approximately 16% variant alleles in blood samples. Her father exhibited facial dysmorphism, including right-sided downslanting palpebral fissure, thin eyelashes, flat zygoma, big mouth, and mild retrognathia, but did not have coloboma or hearing loss.
In a mother and daughter (patients 2 and 3) with Treacher Collins syndrome (TCS4; 618939), Sanchez et al. (2020) identified heterozygosity for a c.2046T-A transversion (c.2046T-A, NM_019014.5) in exon 12 of the POLR1B gene, resulting in a ser682-to-arg (S682R) substitution at a highly conserved residue located in a hydrogen bond that participates in stabilization of the alpha-helix. The mutation was not found in the unaffected father or in the gnomAD database.
Sanchez, E., Laplace-Builhe, B., Mau-Them, F. T., Richard, E., Goldenberg, A., Toler, T. L., Guignard, T., Gatinois, V., Vincent, M., Blanchet, C., Boland, A., Bihoreau, M. T., and 16 others. POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4. Genet. Med. 22: 547-556, 2020. [PubMed: 31649276] [Full Text: https://doi.org/10.1038/s41436-019-0669-9]
Seither, P., Grummt, I. Molecular cloning of RPA2, the gene encoding the second largest subunit of mouse RNA polymerase I. Genomics 37: 135-139, 1996. [PubMed: 8921381] [Full Text: https://doi.org/10.1006/geno.1996.0531]
Stumpf, A. M. Personal Communication. Baltimore, Md. 07/06/2020.