Format

Send to

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

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

Author information

1
Service de Génétique Clinique, centre de référence anomalies du développement et syndromes malformatifs, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Hôpital Arnaud de Villeneuve, Faculté de Médecine, Montpellier, France.
2
IRMB, Univ Montpellier, INSERM, CHU Montpellier, Montpellier, France.
3
Unité Fonctionnelle d'Innovation diagnostique des maladies rares, Pôle de Biologie, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
4
Inserm-Université de Bourgogne UMR1231 GAD, FHU-TRANSLAD, Dijon, France.
5
IRCM, INSERM, U1194 Univ Montpellier, Montpellier, France.
6
Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics, F 76000, Normandy Center for Genomic and Personalized Medicine, Reference Center for Developmental Disorders, Rouen, France.
7
Department of Pediatrics, Division of Genetics & Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
8
Unité de Génétique Chromosomique, Plateforme ChromoStem, Hôpital Arnaud de Villeneuve, CHU Montpellier, Montpellier, France.
9
Service de génétique médicale, CHU de Nantes, Nantes, France.
10
Service ORL, Montpellier, France.
11
Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France.
12
Institute of Human Genetics, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
13
Department of Medical Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
14
ORL CH d'Evreux, Évreux, France.
15
Service d'ORL pédiatrique, Hôpital Universitaire Necker-Enfants Malades, APHP et François Jacob, CEA, Université Paris-Saclay, Evry, France.
16
Laboratoire de Génétique Moléculaire, Plateau technique de Biologie - CHU Dijon, Dijon, France.
17
UF de Génétique Moléculaire, Service de Biochimie et Biologie Moléculaire, Hôpital Lariboisière, Paris, France.
18
Chirurgie plastique infantile Montpellier, Montpellier, France.
19
IRMB, Univ Montpellier, INSERM, CHU Montpellier, Montpellier, France. florence.apparailly@inserm.fr.

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.

KEYWORDS:

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

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center