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Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant.

  • Di Donato N Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA. Electronic address: nataliya.didonato@uniklinikum-dresden.de.
  • Jean YY Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
  • Maga AM Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98105, USA; Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
  • Krewson BD Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
  • Shupp AB Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
  • Avrutsky MI Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
  • Roy A Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
  • Collins S Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
  • Olds C Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
  • Willert RA Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
  • Czaja AM Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
  • Johnson R Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
  • Stover JA Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
  • Gottlieb S Division of Pediatric Neurology, Nemours Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA.
  • Bartholdi D Department of Human Genetics, Inselspital, 3010 Bern, Switzerland.
  • Rauch A Institute of Medical Genetics, University of Zurich, 8952 Schlieren, Switzerland.
  • Goldstein A Department of Pediatrics, School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA.
  • Boyd-Kyle V Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
  • Aldinger KA Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
  • Mirzaa GM Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
  • Nissen A Medical Genetics Center, 80335 Munich, Germany.
  • Brigatti KW Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA; Clinic for Special Children, Strasburg, PA 17579, USA.
  • Puffenberger EG Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA; Clinic for Special Children, Strasburg, PA 17579, USA.
  • Millen KJ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
  • Strauss KA Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA; Clinic for Special Children, Strasburg, PA 17579, USA; Lancaster General Hospital, Lancaster, PA 17602, USA.
  • Dobyns WB Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Neurology, University of Washington, Seattle, WA 98195, USA.
  • Troy CM Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; The Taub Institute for Research on Alzheimer Disease and the Aging Brain, Columbia University Medical Center; Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
  • Jinks RN Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA. Electronic address: rjinks@fandm.edu.
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  • 2016-11-05
Published in:
  • American journal of human genetics. - 2016
MCD
apoptosis
epilepsy
intellectual disability
malformation of cortical development
mouse model
neurodevelopmental disorder
pachygyria
Amyloid beta-Peptides
Animals
Apoptosis
CRADD Signaling Adaptor Protein
Caspase 2
Cell Survival
Cloning, Molecular
Cognition
Cysteine Endopeptidases
Dendritic Cells
Ethnic Groups
Genes, Recessive
Genome-Wide Association Study
HEK293 Cells
Humans
Immunoprecipitation
Lissencephaly
Megalencephaly
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Neurons
PC12 Cells
Rats
Signal Transduction
English Lissencephaly is a malformation of cortical development typically caused by deficient neuronal migration resulting in cortical thickening and reduced gyration. Here we describe a "thin" lissencephaly (TLIS) variant characterized by megalencephaly, frontal predominant pachygyria, intellectual disability, and seizures. Trio-based whole-exome sequencing and targeted re-sequencing identified recessive mutations of CRADD in six individuals with TLIS from four unrelated families of diverse ethnic backgrounds. CRADD (also known as RAIDD) is a death-domain-containing adaptor protein that oligomerizes with PIDD and caspase-2 to initiate apoptosis. TLIS variants cluster in the CRADD death domain, a platform for interaction with other death-domain-containing proteins including PIDD. Although caspase-2 is expressed in the developing mammalian brain, little is known about its role in cortical development. CRADD/caspase-2 signaling is implicated in neurotrophic factor withdrawal- and amyloid-β-induced dendritic spine collapse and neuronal apoptosis, suggesting a role in cortical sculpting and plasticity. TLIS-associated CRADD variants do not disrupt interactions with caspase-2 or PIDD in co-immunoprecipitation assays, but still abolish CRADD's ability to activate caspase-2, resulting in reduced neuronal apoptosis in vitro. Homozygous Cradd knockout mice display megalencephaly and seizures without obvious defects in cortical lamination, supporting a role for CRADD/caspase-2 signaling in mammalian brain development. Megalencephaly and lissencephaly associated with defective programmed cell death from loss of CRADD function in humans implicate reduced apoptosis as an important pathophysiological mechanism of cortical malformation. Our data suggest that CRADD/caspase-2 signaling is critical for normal gyration of the developing human neocortex and for normal cognitive ability.
Language
  • English
Open access status
hybrid
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Persistent URL
https://sonar.ch/global/documents/185536
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