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

被引：59

作者：

Sanchez, Elodie ^{[1
,2
]}

Laplace-Builhe, Beryl ^{[2
]}

Mau-Them, Frederic Tran ^{[1
,2
,3
,4
]}

Richard, Eric ^{[5
]}

Goldenberg, Alice ^{[6
,7
]}

Toler, Tomi L. ^{[8
]}

Guignard, Thomas ^{[9
]}

Gatinois, Vincent ^{[9
]}

Vincent, Marie ^{[10
]}

Blanchet, Catherine ^{[11
]}

Boland, Anne ^{[12
]}

Bihoreau, Marie Therese ^{[12
]}

Deleuze, Jean-Francois ^{[12
]}

Olaso, Robert ^{[12
]}

Nephi, Walton ^{[8
]}

Luedecke, Hermann-Josef ^{[13
]}

Verheij, Joke B. G. M. ^{[14
]}

Moreau-Lenoir, Florence ^{[15
]}

Denoyelle, Francoise ^{[16
,17
]}

Riviere, Jean-Baptiste ^{[18
]}

Laplanche, Jean-Louis ^{[19
]}

Willing, Marcia ^{[8
]}

Captier, Guillaume ^{[20
]}

Apparailly, Florence ^{[2
]}

Wieczorek, Dagmar ^{[13
]}

Collet, Corinne ^{[19
]}

Djouad, Farida ^{[2
]}

Genevieve, David ^{[1
,2
]}

机构：

[1] Hop Arnaud Villeneuve, Ctr Reference Anomalies Dev & Syndromes Malformat, Dept Genet Med Malad Rares & Med Personnalisee, Serv Genet Clin,Fac Med, Montpellier, France

[2] Univ Montpellier, INSERM, CHU Montpellier, IRMB, Montpellier, France

[3] CHU Dijon Bourgogne, FHU TRANSLAD, Unite Fonctionnelle Innovat Diagnost Malad Rares, Pole Biol, Dijon, France

[4] Univ Bourgogne, INSERM, UMR1231, GAD,FHU TRANSLAD, Dijon, France

[5] Univ Montpellier, INSERM, U1194, IRCM, Montpellier, France

[6] Normandie Univ, UNIROUEN, INSERM, U1245, Rouen, France

[7] Rouen Univ Hosp, Dept Genet, Normandy Ctr Genom & Personalized Med, Reference Ctr Dev Disorders, F-76000 Rouen, France

[8] Washington Univ, Sch Med, Dept Pediat, Div Genet & Genom Med, St Louis, MO 63110 USA

[9] CHU Montpellier, Hop Arnaud Villeneuve, Unite Genet Chromos, Plateforme ChromoStem, Montpellier, France

[10] CHU Nantes, Serv Genet Med, Nantes, France

[11] Serv ORL, Montpellier, France

[12] Univ Paris Saclay, CEA, Inst Biol Francois Jacob, CNRGH, Evry, France

[13] Heinrich Heine Univ, Med Fac, Inst Human Genet, Dusseldorf, Germany

[14] Univ Groningen, Univ Med Ctr Groningen, Dept Med Genet, Groningen, Netherlands

[15] ORL CH Evreux, Evreux, France

[16] Univ Paris Saclay, Hop Univ Necker Enfants Malades, AP HP, Serv ORL Pediat, Evry, France

[17] Univ Paris Saclay, CEA, Francois Jacob, Evry, France

[18] CHU Dijon, Lab Genet Mol, Plateau Tech Biol, Dijon, France

[19] Hop Lariboisiere, Serv Biochim & Biol Mol, UF Genet Mol, Paris, France

[20] Chirurg Plast Infantile Montpellier, Montpellier, France

来源：

GENETICS IN MEDICINE | 2020年 / 22卷 / 03期

关键词：

Treacher Collins-Franceschetti; POLR1B; apoptosis; neural crest cells; TCOF1; GENE-PRODUCT; RIBOSOMAL-RNA; COLLINSSYNDROME; TREACHER; DYSOSTOSIS; TOOLS; P53;

D O I：

10.1038/s41436-019-0669-9

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：547 / 556

页数：10

共 28 条

[1]

[Anonymous], 1996, NAT GENET, V12, P130

[2] Perturbation of rRNA synthesis in the bap28 mutation leads to apoptosis mediated by p53 in the zebrafish central nervous system [J].