Alternative titles; symbols
HGNC Approved Gene Symbol: POLR1D
Cytogenetic location: 13q12.2 Genomic coordinates (GRCh38) : 13:27,620,743-27,667,411 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q12.2 | Treacher Collins syndrome 2 | 613717 | Autosomal dominant; Autosomal recessive | 3 |
Using mouse Rpa40 (POLR1C; 610060) as bait in a yeast 2-hybrid system, Yao et al. (1996) cloned mouse Polr1d, which they called Rpa16. The deduced 133-amino acid protein has a calculated molecular mass of 15.1 kD. It shares 45% amino acid identity with the yeast subunit Ac19 of RNA polymerases I and III. SDS-PAGE and Western blot analysis showed that Rpa16 encodes the 16-kD subunit of mouse RNA polymerase I.
Amberger (2011) found that the mouse Polr1d sequence (GenBank D86609) reported by Yao et al. (1996) shares 92% identity with variant 1 of the human POLR1D gene (GenBank NM_015972), which maps to chromosome 13q12.2 (GRCh37).
Using yeast 2-hybrid analysis, Yao et al. (1996) showed that mouse Rpa16 interacted with mouse Rpa40, and mutation analysis revealed that the alpha motif of Rpa40 was required for the interaction. Neither Rpa40 nor Rpa16 could self-associate in the yeast 2-hybrid system.
In a 3-year-old boy with Treacher Collins syndrome (TCS2; 613717) who was negative for mutation in the TCOF1 gene (606847), Dauwerse et al. (2011) performed genomewide copy number analysis and identified a 156-kb de novo deletion at chromosome 13q12.2 that encompassed the entire POLR1D gene and exon 1 of the LNX2 gene (609733). Sequence analysis of POLR1D and LNX2 in 10 additional Treacher Collins patients who were negative for mutations in TCOF1 revealed a boy who was heterozygous for a nonsense mutation in POLR1D (R87X; 613715.0001). Analysis of POLR1D in a further 242 individuals with typical TCS or with clinical findings in the TCS phenotypic spectrum who were negative for TCOF1 mutations yielded 10 heterozygous nonsense mutations and 7 heterozygous missense mutations in 20 index cases (see, e.g., 613715.0002-613715.0006). Nineteen of the 20 mutations were in exon 3 of the POLR1D gene; 1 patient had a splice site mutation in intron 2.
Schaefer et al. (2014) reported 4 affected children from 2 unrelated consanguineous families with mild Treacher Collins syndrome who shared the same homozygous missense mutation in the POLR1D gene (L55V; 613715.0007). This mutation was localized to the region encoding the dimerization domain of the RNA polymerase. A functional analysis of TCOF1 by real-time quantitative RT-PCR was performed in the first family, demonstrating a 50% reduction of transcripts in the index case, compatible with the hypothesis that this mutation impairs RNA polymerase and results in a lower amount of mature dimeric ribosomes.
In the probands from 3 unrelated families with Treacher Collins syndrome-2 (TCS2; 613717), Dauwerse et al. (2011) identified heterozygosity for a c.259C-T transition in exon 3 of the POLR1D gene, resulting in an arg87-to-ter (R87X) substitution. The mutation was not found in 280 controls. Two families demonstrated nonpenetrance: in 1 family, there were 2 affected brothers as well as 3 unaffected family members (their father, his twin brother, and the paternal grandfather) who carried the mutation. In another family, the mutation was present in an affected brother and sister and the sister's affected daughter, as well as their unaffected mother.
In 2 brothers and an unrelated proband with Treacher Collins syndrome-2 (TCS2; 613717), Dauwerse et al. (2011) identified heterozygosity for a c.139G-A transition in exon 3 of the POLR1D gene, resulting in a glu47-to-lys (E47K) substitution at an evolutionarily conserved residue in the RNA polymerase dimerization domain of POLR1D. The mutation, which was not found in 280 controls, was predicted to disrupt dimerization of the alpha subunits.
In a mother and 2 daughters with Treacher Collins syndrome-2 (TCS2; 613717), Dauwerse et al. (2011) identified heterozygosity for a c.152T-G transversion in exon 3 of the POLR1D gene, resulting in a leu51-to-arg (L51R) substitution at an evolutionarily conserved residue in the RNA polymerase dimerization domain of POLR1D. The mutation, which was not found in 280 controls, was predicted to disrupt dimerization of the alpha subunits.
In a 3-generation family segregating autosomal dominant Treacher Collins syndrome-2 (TCS2; 613717), Dauwerse et al. (2011) identified heterozygosity for a 2-bp deletion (c.326delCA) in exon 3 of the POLR1D gene, predicted to cause a frameshift resulting in a premature termination codon. The mutation was present in 3 affected family members, the proband, his father, and his paternal grandfather; it was not found in 280 controls. The proband's only manifestation of TCS was mandibular hypoplasia.
In a father and daughter with Treacher Collins syndrome-2 (TCS2; 613717), Dauwerse et al. (2011) identified heterozygosity for a 2-bp duplication (c.263dupG) in exon 3 of the POLR1D gene, predicted to cause a frameshift resulting in a premature termination codon. The mutation was not found in 280 controls.
In a mother and daughter with Treacher Collins syndrome-2 (TCS2; 613717), Dauwerse et al. (2011) identified heterozygosity for a 2-bp insertion (c.88insTG) in exon 3 of the POLR1D gene, resulting in a frameshift and premature termination codon. The mutation was not found in 280 controls.
In 4 affected children from 2 unrelated consanguineous families with mild Treacher Collins syndrome (TCS2; 613717), Schaefer et al. (2014) identified a homozygous c.163C-G transversion resulting in a leu55-to-val (L55V) substitution in the POLR1D gene that was localized to the region encoding the dimerization domain of the RNA polymerase. Both sets of unaffected parents and the unaffected sister of the first proband were heterozygous for the mutation. The mutation was not found in a series of 150 control chromosomes and was not observed in the 1000 Genomes Project or Exome Variant Server databases. The leucine at position 55 is highly conserved across species. This mutation is located in exon 3 of the POLR1D gene, within the hotspot of 8 mutations between amino acids 45 and 57. Haplotype analysis supported the hypothesis that this mutation in the 2 families arose independently and not from a founder effect.
Amberger, J. S. Personal Communication. Baltimore, Maryland 1/28/2011.
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]
Schaefer, E., Collet, C., Genevieve, D., Vincent, M., Lohmann, D. R., Sanchez, E., Bolender, C., Eliot, M.-M., Nurnberg, G., Passos-Bueno, M.-R., Wieczorek, D., Van Maldergem, L., Doray, B. Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome. Genet. Med. 16: 720-724, 2014. [PubMed: 24603435] [Full Text: https://doi.org/10.1038/gim.2014.12]
Yao, Y., Yamamoto, K, Nishi, Y., Nogi, Y., Muramatsu, M. Mouse RNA polymerase I 16-kDa subunit able to associate with 40-kDa subunit is a homolog of yeast AC19 subunit of RNA polymerases I and III. J. Biol. Chem. 271: 32881-32885, 1996. [PubMed: 8955128] [Full Text: https://doi.org/10.1074/jbc.271.51.32881]