Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features

Zaki, Maha S.; Accogli, Andrea; Mirzaa, Ghayda; Rahman, Fatima; Mohammed, Hiba; Porras-Hurtado, Gloria Liliana; Efthymiou, Stéphanie; Maqbool, Shazia; Shukla, Anju; Vincent, John B.; Hussain, A.; Mir, Asif; Beetz, Christian; Leubauer, Anika; Houlden, Henry; Gleeson, Joseph G.; Maroofian, Reza

doi:10.1038/s41431-021-00910-0

Cited by 9 publications

(6 citation statements)

References 27 publications

(43 reference statements)

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“…Genetic evidence clearly links perturbations of each of the PIDDosome components to neurodevelopmental or neurodegenerative phenotypes. Loss-of-function mutations in RAIDD and PIDD1 which prevent PIDDosome activation are associated with lissencephaly [ 78–82 ], a form of impaired cortical development, and intellectual disability [ 83 , 84 ]. Even though the circumstances which lead to the activation of the PIDDosome in the brain or the cell type where this becomes relevant are not known, the authors speculate that apoptosis induced by the PIDDosome might be critical for proper cortical development [ 85 , 86 ].…”

Section: Emerging Pathologicial and Physiolocial Roles Of Pidd1mentioning

confidence: 99%

PIDD1 in cell cycle control, sterile inflammation and cell death

Weiler

Szabó

Villunger

2022

Biochemical Society Transactions

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The death fold domain-containing protein PIDD1 has recently attracted renewed attention as a regulator of the orphan cell death-related protease, Caspase-2. Caspase-2 can activate p53 to promote cell cycle arrest in response to centrosome aberrations, and its activation requires formation of the PIDDosome multi-protein complex containing multimers of PIDD1 and the adapter RAIDD/CRADD at its core. However, PIDD1 appears to be able to engage with multiple client proteins to promote an even broader range of biological responses, such as NF-κB activation, translesion DNA synthesis or cell death. PIDD1 shows features of inteins, a class of self-cleaving proteins, to create different polypeptides from a common precursor protein that allow it to serve these diverse functions. This review summarizes structural information and molecular features as well as recent experimental advances that highlight the potential pathophysiological roles of this unique death fold protein to highlight its drug-target potential.

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Section: Emerging Pathologicial and Physiolocial Roles Of Pidd1mentioning

confidence: 99%

PIDD1 in cell cycle control, sterile inflammation and cell death

Weiler

Szabó

Villunger

2022

Biochemical Society Transactions

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“…In the past few years, biallelic pathogenic variants in CRADD and PIDD1 have been associated with LIS, anterior-predominant pachygyria, and ID (Table 1 ) [ 7 – 9 , 27 – 32 ]. This finding has drawn attention to the PIDDosome complex, suggesting additional biological functions aside from DNA-damage induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Zaki et al reported 11 patients with biallelic pathogenic variants in the PIDD1 gene [ 9 ]. All patients exhibited DD, and variable degree of ID.…”

Section: Discussionmentioning

confidence: 99%

“…In 2016, Di Donato et al showed CRADD biallelic loss of function variants as causal for LIS with megalencephaly, ID, and defined hallmark features of CRADD-associated phenotypes that include fronto-temporal predominant pachygyria-agyria with mild cortical thickening (OMIM: 614499) [ 7 ]. Recently, homozygous pathogenic variants in PIDD1 have been reported in patients with non-syndromic ID (OMIM: 619827) [ 8 ], several neuropsychiatric and behavioral abnormalities, and a “CRADD-like” anterior-predominant pachygyria pattern in neuroimaging [ 9 ]. However, to date, the CASP2 gene has not been associated with a human phenotype (OMIM: 600639).…”

Section: Introductionmentioning

confidence: 99%

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Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly

Uctepe,

Vona,

Esen

et al. 2023

Eur J Hum Genet

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Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function.

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“…However, nucleolin has been shown to interact with the death domain of the p53-induced protein death domain (PIDD) protein 1 [ 24 ]. Recently, we, and others, have reported homozygous PIDD1 mutations segregating in autosomal recessive non-syndromic intellectual disability [ 15 , 25 , 26 , 27 ]. Mutations in the gene encoding the PIDD-interactor, CRADD, have also been linked to autosomal recessive intellectual disability and lissencephaly [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Heterozygous De Novo Truncating Mutation of Nucleolin in an ASD Individual Disrupts Its Nucleolar Localization

Sheikh

Harripaul

Vasli

et al. 2021

Genes

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Nucleolin (NCL/C23; OMIM: 164035) is a major nucleolar protein that plays a critical role in multiple processes, including ribosome assembly and maturation, chromatin decondensation, and pre-rRNA transcription. Due to its diverse functions, nucleolin has frequently been implicated in pathological processes, including cancer and viral infection. We recently identified a de novo frameshifting indel mutation of NCL, p.Gly664Glufs*70, through whole-exome sequencing of autism spectrum disorder trios. Through the transfection of constructs encoding either a wild-type human nucleolin or a mutant nucleolin with the same C-terminal sequence predicted for the autism proband, and by using co-localization with the nucleophosmin (NPM; B23) protein, we have shown that the nucleolin mutation leads to mislocalization of the NCL protein from the nucleolus to the nucleoplasm. Moreover, a construct with a nonsense mutation at the same residue, p.Gly664*, shows a very similar effect on the location of the NCL protein, thus confirming the presence of a predicted nucleolar location signal in this region of the NCL protein. Real-time fluorescence recovery experiments show significant changes in the kinetics and mobility of mutant NCL protein in the nucleoplasm of HEK293Tcells. Several other studies also report de novo NCL mutations in ASD or neurodevelopmental disorders. The altered mislocalization and dynamics of mutant NCL (p.G664Glufs*70/p.G664*) may have relevance to the etiopathlogy of NCL-related ASD and other neurodevelopmental phenotypes.

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Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features

Cited by 9 publications

References 27 publications

PIDD1 in cell cycle control, sterile inflammation and cell death

PIDD1 in cell cycle control, sterile inflammation and cell death

Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly

Heterozygous De Novo Truncating Mutation of Nucleolin in an ASD Individual Disrupts Its Nucleolar Localization

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