TY - JOUR
T1 - Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability
AU - Sheikh, Taimoor I.
AU - Vasli, Nasim
AU - Pastore, Stephen
AU - Kharizi, Kimia
AU - Harripaul, Ricardo
AU - Fattahi, Zohreh
AU - Pande, Shruti
AU - Naeem, Farooq
AU - Hussain, Abrar
AU - Mir, Asif
AU - Islam, Omar
AU - Girisha, Katta Mohan
AU - Irfan, Muhammad
AU - Ayub, Muhammad
AU - Schwarzer, Christoph
AU - Najmabadi, Hossein
AU - Shukla, Anju
AU - Sladky, Valentina C.
AU - Braun, Vincent Zoran
AU - Garcia-Carpio, Irmina
AU - Villunger, Andreas
AU - Vincent, John B.
N1 - Funding Information:
This research project was supported by grants from the Canadian Institutes for Health Research MOP-102758 and PJT-156402, to J.B.V., a NARSAD Young Investigator Award to N.V., also a grant from the Iran National Science Foundation (INSF); grant No.920384578, to H.N. A.V. acknowledges support by the Austrian Science Fund, FWF (PIR-3) as well as the ERC Advanced Grant “POLICE” (#787171). A.S. acknowledges funding support from the National Institutes of Health (NIH), Grant number:1R01HD093570-01A1. We thank LL Fava for providing PIDD1 KO cell lines. We are also most grateful for the participation of our patients and their families. The authors wish to acknowledge the resources of MSSNG (research.mss.ng), Autism Speaks and The Centre for Applied Genomics at The Hospital for Sick Children, Toronto, Canada. We also thank the participating families for their time and contributions to this database, as well as the generosity of the donors who supported this program. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript, including dbGAP accession phs000424.v8. p2, were obtained from the GTEx Portal on 20 November 2020. We acknowledge the contribution of the Allen Institute for Brain Science and the BrainSpan Consortium Members for the transcriptomic reference atlases of the fetal and adult human brain, and the Linarsson lab for the mouse brain atlas. We thank Dr. Leon French (CAMH) for assistance with transcriptomic analyses.
Publisher Copyright:
© 2021, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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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U2 - 10.1038/s41398-020-01158-w
DO - 10.1038/s41398-020-01158-w
M3 - Article
AN - SCOPUS:85098891220
SN - 2158-3188
VL - 11
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 1
ER -