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. Epub 2015 Apr 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / genetics
  • Genotype
  • Humans
  • Limb Deformities, Congenital / genetics*
  • Limb Deformities, Congenital / physiopathology
  • Mandibulofacial Dysostosis / genetics*
  • Mandibulofacial Dysostosis / physiopathology
  • Mutation
  • Neural Crest / growth & development
  • Neural Crest / pathology
  • RNA Polymerase I / genetics*
  • Ribosomes / genetics*
  • Ribosomes / pathology
  • Zebrafish


  • RNA Polymerase I