Journal article
Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability
Translational psychiatry, v 11(1), pp 1-13
05 Jan 2021
PMID: 33414379
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
PIDD1 encodes p53-Induced Death Domain protein 1, which acts as a sensor surveilling centrosome numbers and p53 activity in mammalian cells. Early results also suggest a role in DNA damage response where PIDD1 may act as a cell-fate switch, through interaction with RIP1 and NEMO/IKKg, activating NF-κB signaling for survival, or as an apoptosis-inducing protein by activating caspase-2. Biallelic truncating mutations in CRADD-the protein bridging PIDD1 and caspase-2-have been reported in intellectual disability (ID), and in a form of lissencephaly. Here, we identified five families with ID from Iran, Pakistan, and India, with four different biallelic mutations in PIDD1, all disrupting the Death Domain (DD), through which PIDD1 interacts with CRADD or RIP1. Nonsense mutations Gln863* and Arg637* directly disrupt the DD, as does a missense mutation, Arg815Trp. A homozygous splice mutation in the fifth family is predicted to disrupt splicing upstream of the DD, as confirmed using an exon trap. In HEK293 cells, we show that both Gln863* and Arg815Trp mutants fail to co-localize with CRADD, leading to its aggregation and mis-localization, and fail to co-precipitate CRADD. Using genome-edited cell lines, we show that these three PIDD1 mutations all cause loss of PIDDosome function. Pidd1 null mice show decreased anxiety, but no motor abnormalities. Together this indicates that PIDD1 mutations in humans may cause ID (and possibly lissencephaly) either through gain of function or secondarily, due to altered scaffolding properties, while complete loss of PIDD1, as modeled in mice, may be well tolerated or is compensated for.
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Details
- Title
- Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability
- Creators
- Taimoor I Sheikh - Centre for Addiction and Mental HealthNasim Vasli - Hospital for Sick ChildrenStephen Pastore - Centre for Addiction and Mental HealthKimia Kharizi - University of Social Welfare and Rehabilitation SciencesRicardo Harripaul - University of TorontoZohreh Fattahi - University of Social Welfare and Rehabilitation SciencesShruti Pande - Manipal Academy of Higher EducationFarooq Naeem - Centre for Addiction and Mental HealthAbrar Hussain - International Islamic University, IslamabadAsif Mir - International Islamic University, IslamabadOmar Islam - Queen's UniversityKatta Mohan Girisha - Manipal Academy of Higher EducationMuhammad Irfan - Riphah International UniversityMuhammad Ayub - Queen's UniversityChristoph Schwarzer - Innsbruck Medical UniversityHossein Najmabadi - University of Social Welfare and Rehabilitation SciencesAnju Shukla - Manipal Academy of Higher EducationValentina C Sladky - Universität InnsbruckVincent Zoran Braun - Innsbruck Medical UniversityIrmina Garcia-Carpio - Universität InnsbruckAndreas Villunger - Innsbruck Medical UniversityTaimoor I Sheikh - Drexel University, Pathology (and Laboratory Medicine)John B Vincent - University of Toronto
- Publication Details
- Translational psychiatry, v 11(1), pp 1-13
- Publisher
- Nature Publishing Group
- Grant note
- 1R01HD093570-01A1 / U.S. Department of Health & Human Services | NIH | Center for Information Technology (Center for Information Technology, National Institutes of Health) PJT-156402 / Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) MOP-102758 / Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) n/a / Brain and Behavior Research Foundation (Brain & Behavior Research Foundation) R01 HD093570 / NICHD NIH HHS FWF (PIR-3) / Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung) POLICE / EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) 920384578 / Iran National Science Foundation (INSF)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pathology (and Laboratory Medicine)
- Web of Science ID
- WOS:000610154900001
- Scopus ID
- 2-s2.0-85098891220
- Other Identifier
- 991022093054204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Psychiatry