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. Epub 2016 Oct 20.


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.

MeSH terms

  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Apoptosis*
  • CRADD Signaling Adaptor Protein / genetics*
  • Caspase 2 / genetics
  • Caspase 2 / metabolism*
  • Cell Survival
  • Cloning, Molecular
  • Cognition
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • Dendritic Cells / metabolism
  • Ethnic Groups / genetics
  • Genes, Recessive
  • Genome-Wide Association Study
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Lissencephaly / genetics*
  • Megalencephaly / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Neurons / metabolism*
  • PC12 Cells
  • Rats
  • Signal Transduction


  • Amyloid beta-Peptides
  • CRADD Signaling Adaptor Protein
  • CRADD protein, human
  • CASP2 protein, human
  • Caspase 2
  • Cysteine Endopeptidases