Acrofacial Dysostosis, Cincinnati Type, a Mandibulofacial Dysostosis Syndrome with Limb Anomalies, Is Caused by POLR1A Dysfunction.
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.
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.
K Nicole
KN
Weaver
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.
Kristin E Noack
KE
Watt
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.
Robert B
RB
Hufnagel
Stowers Institute for Medical Research, 1000 East 50(th) Street, Kansas City, MI 64110, USA.
Joaquin
J
Navajas Acedo
Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Luke L
LL
Linscott
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.
Kristen L
KL
Sund
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.
Patricia L
PL
Bender
Institut für Humangenetik, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60596 Frankfurt, Germany.
Rainer
R
König
Neurogenetics Unit, Clinics Hospital of Ribeirao Preto, University of Sao Paulo, Avenue Bandeirantes 3900, Sao Paulo 14049-900, Brazil.
Charles M
CM
Lourenco
Zentrum für Humangenetik, Universitätsklinikum Regensburg, Franz-Josef-StrauB-Allee 11, 93053 Regensburg, Germany.
Ute
U
Hehr
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.
Robert J
RJ
Hopkin
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr 55, 45122 Essen, Germany.
Dietmar R
DR
Lohmann
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.
Paul A
PA
Trainor
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr 55, 45122 Essen, Germany.
Dagmar
D
Wieczorek
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.
Howard M
HM
Saal
D000818:Animals; D016923:Cell Death / Q000235:genetics; D005838:Genotype; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000503:physiopathology; D008342:Mandibulofacial Dysostosis / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D009432:Neural Crest / Q000254:growth & development / Q000473:pathology; D012318:RNA Polymerase I / Q000235:genetics*; D012270:Ribosomes / Q000235:genetics* / Q000473:pathology; D015027:Zebrafish
D012318:RNA Polymerase I