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

Di Donato, Nataliya; Jean, Ying Y; Maga, A Murat; Krewson, Briana D; Shupp, Alison B; Avrutsky, Maria I; Roy, Achira; Collins, Sarah; Olds, Carissa; Willert, Rebecca A; Czaja, Agnieszka M; Johnson, Rachel; Stover, Jessi A; Gottlieb, Steven; Bartholdi, Deborah; Rauch, Anita; Goldstein, Amy; Boyd-Kyle, Victoria; Aldinger, Kimberly A; Mirzaa, Ghayda M; ... (2016). Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant. American journal of human genetics, 99(5), pp. 1117-1129. Cell Press 10.1016/j.ajhg.2016.09.010

1-s2.0-S0002929716303901-main.pdf - Published Version
Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND).

Download (1MB) | Preview

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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Humangenetik

UniBE Contributor:

Bartholdi, Deborah


600 Technology > 610 Medicine & health




Cell Press




André Schaller

Date Deposited:

04 Jun 2018 15:54

Last Modified:

27 Oct 2019 02:27

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

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




Actions (login required)

Edit item Edit item
Provide Feedback