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

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

  • Am J Hum Genet. 2016 Nov 3;99(5):1117-1129. doi: 10.1016/j.ajhg.2016.09.010.
Nataliya Di Donato 1,  Ying Y Jean 2,  A Murat Maga 3,  Briana D Krewson 4,  Alison B Shupp 4,  Maria I Avrutsky 2,  Achira Roy 5,  Sarah Collins 5,  Carissa Olds 5,  Rebecca A Willert 4,  Agnieszka M Czaja 4,  Rachel Johnson 4,  Jessi A Stover 4,  Steven Gottlieb 6,  Deborah Bartholdi 7,  Anita Rauch 8,  Amy Goldstein 9,  Victoria Boyd-Kyle 4,  Kimberly A Aldinger 5,  Ghayda M Mirzaa 10,  Anke Nissen 11,  Karlla W Brigatti 12,  Erik G Puffenberger 12,  Kathleen J Millen 5,  Kevin A Strauss 13,  William B Dobyns 14,  Carol M Troy 15,  Robert N Jinks 16
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
  • 3 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.
  • 4 Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
  • 5 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
  • 6 Division of Pediatric Neurology, Nemours Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA.
  • 7 Department of Human Genetics, Inselspital, 3010 Bern, Switzerland.
  • 8 Institute of Medical Genetics, University of Zurich, 8952 Schlieren, Switzerland.
  • 9 Department of Pediatrics, School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA.
  • 10 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
  • 11 Medical Genetics Center, 80335 Munich, Germany.
  • 12 Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA; Clinic for Special Children, Strasburg, PA 17579, USA.
  • 13 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.
  • 14 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.
  • 15 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.
  • 16 Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA. Electronic address: rjinks@fandm.edu.
PMID: 27773430 DOI: 10.1016/j.ajhg.2016.09.010
Abstract

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.

Keywords

MCD; apoptosis; epilepsy; intellectual disability; malformation of cortical development; mouse model; neurodevelopmental disorder; pachygyria.

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