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

Elodie Sanchez, Béryl Laplace-Builhé, Frédéric Tran Mau-Them, Eric Richard, Alice Goldenberg, Tomi L. Toler, Thomas Guignard, Vincent Gatinois, Marie Vincent, Catherine Blanchet, Anne Boland, Marie Thérèse Bihoreau, Jean Francois Deleuze, Robert Olaso, Walton Nephi, Hermann Josef Lüdecke, Joke B.G.M. Verheij, Florence Moreau-Lenoir, Françoise Denoyelle, Jean Baptiste RivièreJean Louis Laplanche, Marcia Willing, Guillaume Captier, Florence Apparailly, Dagmar Wieczorek, Corinne Collet, Farida Djouad, David Geneviève

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


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.

Original languageEnglish
Pages (from-to)547-556
Number of pages10
JournalGenetics in Medicine
Issue number3
StatePublished - Mar 1 2020


  • POLR1B
  • Treacher Collins–Franceschetti
  • apoptosis
  • neural crest cells


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