Mutations in CRADD result in reduced caspase-2-mediated neuronal apoptosis and cause megalencephaly with a rare lissencephaly variant
| Autor: | Steven Gottlieb, Kevin A. Strauss, Rachel M. Johnson, Kathleen J. Millen, Ying Y. Jean, Deborah Bartholdi, Karlla W. Brigatti, Erik G. Puffenberger, A. Murat Maga, Agnieszka M. Czaja, Sarah Collins, Carol M. Troy, Amy Goldstein, Anke Nissen, Jessi A. Stover, Carissa Olds, Alison B. Shupp, Achira Roy, Ghayda M. Mirzaa, Robert N. Jinks, Rebecca A. Willert, Kimberly A. Aldinger, Briana D. Krewson, Victoria Boyd-Kyle, William B. Dobyns, Maria I. Avrutsky, Nataliya Di Donato, Anita Rauch |
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| Přispěvatelé: | University of Zurich, Di Donato, Nataliya |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
10039 Institute of Medical Genetics Apoptosis PC12 Cells Mice 0302 clinical medicine Cognition Neurotrophic factors Ethnicity pachygyria Genetics(clinical) Megalencephaly Cloning Molecular 610 Medicine & health Genetics (clinical) Genetics Mice Knockout Neurons Neocortex biology Caspase 2 CRADD Signaling Adaptor Protein Cysteine Endopeptidases medicine.anatomical_structure intellectual disability Lissencephaly Signal Transduction Programmed cell death 2716 Genetics (clinical) Cell Survival mouse model Genes Recessive Article 03 medical and health sciences 1311 Genetics medicine Animals Humans Immunoprecipitation Death domain MCD Amyloid beta-Peptides Pachygyria malformation of cortical development Dendritic Cells medicine.disease neurodevelopmental disorder Rats Mice Inbred C57BL 030104 developmental biology HEK293 Cells Mutation biology.protein epilepsy 570 Life sciences Neuroscience 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | 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 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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