POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies.
RNA Polymerase I
acrofacial dysostosis
congenital heart defect
craniofacial anomalies
developmental delay
epilepsy
limb defects
neural crest cells
ribosomal RNA
ribosomopathies
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
04 05 2023
04 05 2023
Historique:
received:
26
10
2022
accepted:
21
03
2023
medline:
8
5
2023
pubmed:
20
4
2023
entrez:
19
04
2023
Statut:
ppublish
Résumé
Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.
Identifiants
pubmed: 37075751
pii: S0002-9297(23)00098-8
doi: 10.1016/j.ajhg.2023.03.014
pmc: PMC10183370
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
809-825Subventions
Organisme : NHLBI NIH HHS
ID : K08 HL143177
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD028827
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE027091
Pays : United States
Informations de copyright
Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests A.B., M.J.G.S., K. McWalters, R.P., and R.S. are employees of GeneDx.
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