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.
Bibliographical noteFunding Information:
Research reported in this publication was supported by the Deutsche Forschungsgemeinschaft ( DI 2079/2-1 and DI 2170/2-2 to N.D.D.), HHMI Undergraduate Science Education Awards ( 52006294 and 52007538 to Franklin & Marshall College, R.N.J., Principal Investigator), the Center for Research on Women and Newborn Health and ConnectCare3 (to R.N.J.), the National Eye Institute (NEI) of the NIH (Vision Training Grant T32 EY013933 to M.I.A.), and the National Institute of Neurological Disorders and Stroke (NINDS) of the NIH ( K08NS092898 to G.M.M., R01NS081333 to C.M.T., R01NS080390 to K.J.M., and R01NS092772 to W.B.D.). The Clinic for Special Children is funded by charitable contributions from private donors and the communities it serves. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other organizations listed above. The funding sources had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, or decision to submit the manuscript for publication. All authors discussed and commented on the manuscript.
- intellectual disability
- malformation of cortical development
- mouse model
- neurodevelopmental disorder