title: Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant.
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.
authors: 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.
authors: Nataliya
authors: N
authors: Di Donato
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors: Ying Y
authors: YY
authors: Jean
authors: 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.
authors: A Murat
authors: AM
authors: Maga
authors: Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
authors: Briana D
authors: BD
authors: Krewson
authors: Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
authors: Alison B
authors: AB
authors: Shupp
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors: Maria I
authors: MI
authors: Avrutsky
authors: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
authors: Achira
authors: A
authors: Roy
authors: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
authors: Sarah
authors: S
authors: Collins
authors: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
authors: Carissa
authors: C
authors: Olds
authors: Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
authors: Rebecca A
authors: RA
authors: Willert
authors: Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
authors: Agnieszka M
authors: AM
authors: Czaja
authors: Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
authors: Rachel
authors: R
authors: Johnson
authors: Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
authors: Jessi A
authors: JA
authors: Stover
authors: Division of Pediatric Neurology, Nemours Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA.
authors: Steven
authors: S
authors: Gottlieb
authors: Department of Human Genetics, Inselspital, 3010 Bern, Switzerland.
authors: Deborah
authors: D
authors: Bartholdi
authors: Institute of Medical Genetics, University of Zurich, 8952 Schlieren, Switzerland.
authors: Anita
authors: A
authors: Rauch
authors: Department of Pediatrics, School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA.
authors: Amy
authors: A
authors: Goldstein
authors: Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA.
authors: Victoria
authors: V
authors: Boyd-Kyle
authors: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
authors: Kimberly A
authors: KA
authors: Aldinger
authors: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Ghayda M
authors: GM
authors: Mirzaa
authors: Medical Genetics Center, 80335 Munich, Germany.
authors: Anke
authors: A
authors: Nissen
authors: Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA; Clinic for Special Children, Strasburg, PA 17579, USA.
authors: Karlla W
authors: KW
authors: Brigatti
authors: Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA; Clinic for Special Children, Strasburg, PA 17579, USA.
authors: Erik G
authors: EG
authors: Puffenberger
authors: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
authors: Kathleen J
authors: KJ
authors: Millen
authors: 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.
authors: Kevin A
authors: KA
authors: Strauss
authors: 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.
authors: William B
authors: WB
authors: Dobyns
authors: 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.
authors: Carol M
authors: CM
authors: Troy
authors: Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA 17604, USA. Electronic address: rjinks@fandm.edu.
authors: Robert N
authors: RN
authors: Jinks
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053420:CRADD Signaling Adaptor Protein / Q000235:genetics*; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D003001:Cloning, Molecular; D003071:Cognition; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism; D005006:Ethnicity / Q000235:genetics; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D054082:Lissencephaly / Q000235:genetics*; D058627:Megalencephaly / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D053420:CRADD Signaling Adaptor Protein; C104252:CRADD protein, human; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases
keywords: MCD; apoptosis; epilepsy; intellectual disability; malformation of cortical development; mouse model; neurodevelopmental disorder; pachygyria