POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4

Genet Med. 2020 Mar;22(3):547-556. doi: 10.1038/s41436-019-0669-9. Epub 2019 Oct 24.


Purpose: Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2-1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly.

Methods: We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish.

Results: We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives.

Conclusion: Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS.

Keywords: POLR1B; Treacher Collins–Franceschetti; apoptosis; neural crest cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Differentiation / genetics
  • Cell Movement / genetics
  • Craniofacial Abnormalities / genetics*
  • Craniofacial Abnormalities / pathology
  • DNA-Directed RNA Polymerases / genetics*
  • Exome Sequencing
  • Genetic Predisposition to Disease
  • Humans
  • Mandibulofacial Dysostosis / genetics*
  • Mandibulofacial Dysostosis / pathology
  • Mutation
  • Neural Crest / abnormalities
  • Neural Crest / pathology
  • Nuclear Proteins / genetics*
  • Phosphoproteins / genetics*
  • Tumor Suppressor Protein p53 / genetics
  • Zebrafish / genetics


  • Nuclear Proteins
  • Phosphoproteins
  • TCOF1 protein, human
  • Tumor Suppressor Protein p53
  • DNA-Directed RNA Polymerases
  • POLR1C protein, human
  • POLR1D protein, human