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POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies
K. Smallwood, KEN. Watt, S. Ide, K. Baltrunaite, C. Brunswick, K. Inskeep, C. Capannari, MP. Adam, A. Begtrup, DR. Bertola, L. Demmer, E. Demo, O. Devinsky, ER. Gallagher, MJ. Guillen Sacoto, R. Jech, B. Keren, J. Kussmann, R. Ladda, LA. Lansdon,...
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
K08 HL143177
NHLBI NIH HHS - United States
R01 DE027091
NIDCR NIH HHS - United States
K12 HD028827
NICHD NIH HHS - United States
NLK
Cell Press Free Archives
od 1997-01-01 do Před 6 měsíci
Free Medical Journals
od 1949 do Před 6 měsíci
PubMed Central
od 1949 do Před 6 měsíci
Europe PubMed Central
od 1949 do Před 6 měsíci
Open Access Digital Library
od 2005-01-01
- MeSH
- apoptóza MeSH
- crista neuralis patologie MeSH
- fenotyp MeSH
- kraniofaciální abnormality * genetika patologie MeSH
- lidé MeSH
- mandibulofaciální dysostóza * genetika MeSH
- mutageneze MeSH
- myši MeSH
- ribozomy genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
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.
Atrium Health's Levine Children's Hospital Charlotte NC USA
Australian Genomics Melbourne VIC Australia
Department of Anatomy and Cell Biology University of Kansas Medical Center Kansas City KS USA
Department of Clinical Genetics Erasmus MC Rotterdam the Netherlands
Department of Genetics School of Life Science Sokendai Mishima Shizuoka Japan
Department of Neurology P J Safarik University Kosice Slovak Republic
Department of Neurology University Hospital of L Pasteur Kosice Slovak Republic
Department of Pediatrics Penn State Health Children's Hospital Hershey PA USA
Department of Pediatrics The Ohio State University School of Medicine Columbus OH USA
Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH USA
Department of Pediatrics University of Washington Seattle WA USA
Department of Women's Health University of Texas Austin Dell Medical Center Austin TX USA
Division of Developmental Biology Cincinnati Children's Hospital Medical Center Cincinnati OH USA
Division of Human Genetics Cincinnati Children's Hospital Medical Center Cincinnati OH USA
GeneDx LLC Gaithersburg MD USA
Genome Dynamics Laboratory National Institute of Genetics Mishima Shizuoka Japan
Genomic Medicine Center Children's Mercy Research Institute 2401 Gillham Road Kansas City MO USA
Institute of Human Genetics School of Medicine Technical University of Munich Munich Germany
Institute of Neurogenomics Helmholtz Zentrum München Munich Germany
Lehrstuhl für Neurogenetik Technische Universität München Munich Germany
Munich Cluster for Systems Neurology SyNergy Munich Germany
Paediatric Neuroscience Research Group Royal Hospital for Children Glasgow G667AB UK
School of Medicine University of Missouri Kansas City 2411 Holmes Street Kansas City MO USA
Sibley Heart Center Atlanta GA USA
Stowers Institute for Medical Research Kansas City MO USA
The Cancer Institute of JFCR Tokyo Japan
University of Melbourne Melbourne VIC Australia
Citace poskytuje Crossref.org
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