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Article Dans Une Revue Genetics in Medicine Année : 2020

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

Anne Boland

Résumé

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.

Domaines

Génétique

Dates et versions

hal-02549940 , version 1 (21-04-2020)

Identifiants

Citer

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, 2020, 22 (3), pp.547-556. ⟨10.1038/s41436-019-0669-9⟩. ⟨hal-02549940⟩
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