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

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.

How Altered Ribosome Production Can Cause or Contribute to Human Disease: The Spectrum of Ribosomopathies

“…In addition, in 2011, mutations in two genes encoding for Pol I subunits ( POLR1D and POLR1C ) were found mutated in a small number of TCS patients [ 41 ]. More recently, the work of Sanchez et al [ 42 ] reported mutations connected with TCS also in the POLR1B gene. Therefore, all these genes are involved in ribosome biogenesis, and especially in rRNA transcription, so Treacher Collins syndrome may be rightly classified as a pure ribosomopathy.…”

“…Therefore, all these genes are involved in ribosome biogenesis, and especially in rRNA transcription, so Treacher Collins syndrome may be rightly classified as a pure ribosomopathy. With the help of mice and zebrafish carrying mutations for the genes involved, researchers showed that deficient ribosome biogenesis caused a reduced proliferation of the progenitors of the craniofacial skeleton cells, called neural crest cells (NCC) [ 42 , 66 , 67 , 68 ]. It is well known that impaired ribosome biogenesis triggers nucleolar stress with the stabilization of p53 and consequent apoptosis.…”

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

“…Of particular interest is impairment of EMT in patient cells; while likely to derive from delayed differentiation, undergoing an EMT is absolutely essential during neural crest induction as migratory capacity of NCCs is vital for vertebrate development. Defects in NCC migration have been observed in differentiated iNCCs derived from Treacher Collins syndrome (TCS) patients and in mouse models of TCS [36,37,85]. Defective NCC migration in Bardet-Biedl syndrome is thought to underlie the craniofacial phenotype, demonstrating that defective NCC migration can be pathogenic [33,86].…”

“…In vivo, induction of NCCs relies on WNT, BMP, FGF, Activin/TGF-β and Notch/Delta signalling pathways [28][29][30][31][32][33]. Given the very significant role of NCCs in the development of craniofacial structures, a number of craniofacial disorders have been associated with defects in NCC biology including Treacher Collins syndrome, CHARGE syndrome and the spliceosomal craniofacial disorders Nager syndrome (NS) and Richieri-Costa Pereira Syndrome (RCPS) [6,17,24,[34][35][36][37][38][39]. Therefore, it is likely that variants in TXNL4A in BMKS lead to defects particularly affecting NCCs, resulting in a craniofacial phenotype.…”

Génvizsgálat Treacher Collins-szindrómában

“…A POLR1D-gén érintettsége esetén AD és AR öröklődésmenet is előfordulhat. Egy 2020. évi tanulmányban a POLR1B (RNA polymerase I subunit) patogén variánsait találták 6, klinikailag Treacher Collinsszindrómás beteg esetében [8]. Az EFTUD2-(elongation factor Tu GTP-binding domain-containing 2) gén eltéréseit azonosították az úgynevezett Guion-Almeida-típus esetében, mely súlyos, progresszív microcephaliával, intellektuális elmaradással, choanaatresiával, szájpadhasadékkal, szívfejlődési rendellenességekkel, valamint oesophagusatresiával jár [9].…”