RAIDD mutations underlie the pathogenesis of thin lissencephaly (TLIS)

Ha, Hyekyung; Park, Hyun Ho

doi:10.1371/journal.pone.0205042

Cited by 6 publications

(3 citation statements)

References 43 publications

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“…1 ). Mild lissencephaly has also been reported in affected individuals [2][3][4][5][6] , and megalencephaly without obvious cortical lamination defects in Cradd null mice 2 . Together with PIDD1 (p53-Induced Death Domain protein 1), CRADD can activate caspase-2-an endopeptidase thought to regulate apoptosis upon DNA damage in the so-called PIDDosome complex [see ref.…”

Section: Introductionmentioning

confidence: 96%

Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability

et al. 2021

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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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Section: Introductionmentioning

confidence: 96%

Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability

et al. 2021

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“…How these phenotypes are caused is not fully resolved yet. Although these RAIDD variants were found to still bind to PIDD1 in a cellular system overexpressing the respective proteins, in vitro assays showed that these mutations disrupt interaction [92,94]. Either way, the mutated variants of RAIDD failed to activate caspase-2.…”

Section: Caspase-2 and The Piddosome In Neuronal Development And Disementioning

confidence: 97%

“…If the PIDDosome or an alternative complex containing RAIDD facilitates caspase-2 activation in neurons might depend on the upstream signal, yet both proteins were found to play a role in brain development, and mutations identified in patients were associated with mild forms of lissencephaly and intellectual disabilities [92][93][94][95][96].…”

Section: Caspase-2 and The Piddosome In Neuronal Development And Disementioning

confidence: 99%

Uncovering the PIDDosome and caspase-2 as regulators of organogenesis and cellular differentiation

Sladky

Villunger

2020

Cell Death Differ

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The PIDDosome is a multiprotein complex that drives activation of caspase-2, an endopeptidase originally implicated in apoptosis. Yet, unlike other caspases involved in cell death and inflammation, caspase-2 seems to exert additional versatile functions unrelated to cell death. These emerging roles range from control of transcription factor activity to ploidy surveillance. Thus, caspase-2 and the PIDDosome act as a critical regulatory unit controlling cellular differentiation processes during organogenesis and regeneration. These newly established functions of the PIDDosome and its downstream effector render its components attractive targets for drug-development aiming to prevent fatty liver diseases, neurodegenerative disorders or osteoporosis. Facts • Caspase-2 and the PIDDosome are involved in the differentiation of various cell types. • Caspase-2, PIDD1 and RAIDD have roles outside the PIDDosome. • Caspase-2 has nonapoptotic functions.

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