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

Elodie Sanchez 1, 2 Béryl Laplace-Builhé 1 Frédéric Tran Mau-Them 3, 4 Eric Richard 5 Alice Goldenberg 6, 7 Tomi Toler 8 Thomas Guignard 9, 2 Vincent Gatinois 1, 10 Marie Vincent 11 Catherine Blanchet 12, 13 Anne Boland 14 Marie Thérèse Bihoreau 14 Jean-François Deleuze 15, 14 Robert Olaso 16, 14 Walton Nephi 8 Hermann-Josef Lüdecke 17 Joke Verheij 18 Florence Moreau-Lenoir 19 Françoise Denoyelle 20, 21, 14 Jean-Baptiste Rivière 22, 4 Jean-Louis Laplanche 23 Marcia Willing 8 Guillaume Captier 24 Florence Apparailly 1 Dagmar Wieczorek 17 Corinne Collet 23 Farida Djouad 1 David Geneviève 1, 2
Abstract : 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.
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Contributeur : Nathalie Salvy-Cordoba <>
Soumis le : mardi 21 avril 2020 - 18:35:05
Dernière modification le : vendredi 15 mai 2020 - 12:38:04

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Elodie Sanchez, Béryl Laplace-Builhé, Frédéric Tran Mau-Them, Eric Richard, Alice Goldenberg, et al.. POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4. Genetics in Medicine, Nature Publishing Group, 2020, 22 (3), pp.547-556. ⟨10.1038/s41436-019-0669-9⟩. ⟨hal-02549940⟩



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