PUBLICATION
POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4
- Authors
- Sanchez, E., Laplace-Builhé, B., Mau-Them, F.T., Richard, E., Goldenberg, A., Toler, T.L., Guignard, T., Gatinois, V., Vincent, M., Blanchet, C., Boland, A., Bihoreau, M.T., Deleuze, J.F., Olaso, R., Nephi, W., Lüdecke, H.J., Verheij, J.B.G.M., Moreau-Lenoir, F., Denoyelle, F., Rivière, J.B., Laplanche, J.L., Willing, M., Captier, G., Apparailly, F., Wieczorek, D., Collet, C., Djouad, F., Geneviève, D.
- ID
- ZDB-PUB-191029-1
- Date
- 2019
- Source
- Genetics in medicine : official journal of the American College of Medical Genetics 22(3): 547-556 (Journal)
- Registered Authors
- Keywords
- POLR1B, Treacher Collins–Franceschetti, apoptosis, neural crest cells
- 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
- PubMed
- 31649276 Full text @ Genet. Med.
Citation
Sanchez, E., Laplace-Builhé, B., Mau-Them, F.T., Richard, E., Goldenberg, A., Toler, T.L., Guignard, T., Gatinois, V., Vincent, M., Blanchet, C., Boland, A., Bihoreau, M.T., Deleuze, J.F., Olaso, R., Nephi, W., Lüdecke, H.J., Verheij, J.B.G.M., Moreau-Lenoir, F., Denoyelle, F., Rivière, J.B., Laplanche, J.L., Willing, M., Captier, G., Apparailly, F., Wieczorek, D., Collet, C., Djouad, F., Geneviève, D. (2019) POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4. Genetics in medicine : official journal of the American College of Medical Genetics. 22(3):547-556.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping