2. Academic Validation
  3. Acrofacial Dysostosis, Cincinnati Type, a Mandibulofacial Dysostosis Syndrome with Limb Anomalies, Is Caused by POLR1A Dysfunction

Acrofacial Dysostosis, Cincinnati Type, a Mandibulofacial Dysostosis Syndrome with Limb Anomalies, Is Caused by POLR1A Dysfunction

  • Am J Hum Genet. 2015 May 7;96(5):765-74. doi: 10.1016/j.ajhg.2015.03.011.
K Nicole Weaver 1,  Kristin E Noack Watt 2,  Robert B Hufnagel 3,  Joaquin Navajas Acedo 4,  Luke L Linscott 5,  Kristen L Sund 3,  Patricia L Bender 3,  Rainer König 6,  Charles M Lourenco 7,  Ute Hehr 8,  Robert J Hopkin 3,  Dietmar R Lohmann 9,  Paul A Trainor 2,  Dagmar Wieczorek 9,  Howard M Saal 3
Affiliations

Affiliations

  • 1 Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, MLC 4006, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. Electronic address: kathryn.weaver@cchmc.org.
  • 2 Stowers Institute for Medical Research, 1000 East 50(th) Street, Kansas City, MI 64110, USA; University of Kansas Medical Center, Kansas City, MI 66160, USA.
  • 3 Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, MLC 4006, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
  • 4 Stowers Institute for Medical Research, 1000 East 50(th) Street, Kansas City, MI 64110, USA.
  • 5 Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 6 Institut für Humangenetik, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60596 Frankfurt, Germany.
  • 7 Neurogenetics Unit, Clinics Hospital of Ribeirao Preto, University of Sao Paulo, Avenue Bandeirantes 3900, Sao Paulo 14049-900, Brazil.
  • 8 Zentrum für Humangenetik, Universitätsklinikum Regensburg, Franz-Josef-StrauB-Allee 11, 93053 Regensburg, Germany.
  • 9 Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr 55, 45122 Essen, Germany.
PMID: 25913037 DOI: 10.1016/j.ajhg.2015.03.011
Abstract

We report three individuals with a cranioskeletal malformation syndrome that we define as acrofacial dysostosis, Cincinnati type. Each individual has a heterozygous mutation in POLR1A, which encodes a core component of RNA polymerase 1. All three individuals exhibit varying degrees of mandibulofacial dysostosis, and two additionally have limb anomalies. Consistent with this observation, we discovered that polr1a mutant zebrafish exhibited cranioskeletal anomalies mimicking the human phenotype. polr1a loss of function led to perturbed ribosome biogenesis and p53-dependent cell death, resulting in a deficiency of neural-crest-derived skeletal precursor cells and consequently craniofacial anomalies. Our findings expand the genotypic and phenotypic heterogeneity of congenital acrofacial disorders caused by disruption of ribosome biogenesis.

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