Expanding the clinical spectrum associated with the <scp><i>PACS1</i></scp> p.<scp>Arg203Trp</scp> mutational hot‐spot: Two additional Italian patients

Bruno, Lucia Pia; Doddato, Gabriella; Baldassarri, Margherita; Rizzo, Caterina Lo; Resciniti, Sara; Bruttini, Mirella; Lista, Mirjam; Zguro, Kristina; Furini, Simone; Mencarelli, Maria Antonietta; Renieri, Alessandra; Ariani, Francesca

doi:10.1002/ajmg.a.62984

Cited by 4 publications

(4 citation statements)

References 12 publications

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“…Most of these studies do not report how burst duration is affected, with two exceptions: a p.P924L KCNT1 variant was associated with shorter bursts 57 , and no change in burst duration was observed in 16p11.2 duplication or deletion models 61 . The increased network burst duration and decreased synchrony in our system could be related to patient EEG reports (though rare and variable) for both PACS1 syndrome and a strikingly similar PACS2 syndrome of “excess discontinuity”, “generalized slowing”, and “slow wave bursts” 62 – 64 . However, these are very different systems, and it is possible that variable firing patterns in neurons initiate epileptic activity but are not reflected in EEG recordings.…”

Section: Discussionmentioning

confidence: 56%

iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity

Rylaarsdam,

Rakotomamonjy,

Pope

et al. 2024

Nat Commun

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PACS1 syndrome is a neurodevelopmental disorder characterized by intellectual disability and distinct craniofacial abnormalities resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). PACS1 is known to have functions in the endosomal pathway and nucleus, but how the p.R203W variant affects developing neurons is not fully understood. Here we differentiated stem cells towards neuronal models including cortical organoids to investigate the impact of the PACS1 syndrome-causing variant on neurodevelopment. While few deleterious effects were detected in PACS1(+/R203W) neural precursors, mature PACS1(+/R203W) glutamatergic neurons exhibited impaired expression of genes involved in synaptic signaling processes. Subsequent characterization of neural activity using calcium imaging and multielectrode arrays revealed the p.R203W PACS1 variant leads to a prolonged neuronal network burst duration mediated by an increased interspike interval. These findings demonstrate the impact of the PACS1 p.R203W variant on developing human neural tissue and uncover putative electrophysiological underpinnings of disease.

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Section: Discussionmentioning

confidence: 56%

iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity

Rylaarsdam,

Rakotomamonjy,

Pope

et al. 2024

Nat Commun

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“…Although the features of the proposita and her mother are milder than those of many PACS1-NDD individuals (Bruno et al, 2023;Seto et al, 2021)…”

Section: Discussionmentioning

confidence: 95%

“…Although the features of the proposita and her mother are milder than those of many PACS1 ‐NDD individuals (Bruno et al, 2023; Seto et al, 2021), a later report proposes a phenotypic spectrum and underreporting of milder presentations (Martinez‐Monseny et al, 2018). The psychiatric features of the proposita's mother have not been previously described in association with PACS1 ‐NDD; however, few reported individuals are adults, and all carry a variant of Arg203.…”

Section: Discussionmentioning

confidence: 99%

Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?

Moller‐Hansen

Hejla

Lee

et al. 2023

American J of Med Genetics Pt A

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To date, PACS1-neurodevelopmental disorder (PACS1-NDD) has been associated with recurrent variation of Arg203 and is considered diagnostic of PACS1-NDD, an autosomal dominant syndromic intellectual disability disorder. Although incompletely defined, the proposed disease mechanism for this variant is altered PACS1 affinity for its client proteins. Given this proposed mechanism, we hypothesized that PACS1 variants that interfere with binding of adaptor proteins might also give rise to syndromic intellectual disability. Herein, we report a proposita and her mother with phenotypic features overlapping PACS1-NDD and a novel PACS1 variant (NM_018026.3:c.[755C > T];[=], p.(Ser252Phe)) that impedes binding of the adaptor protein GGA3 (Golgi-associated, gamma-adaptin ear-containing, ARF-binding protein 3). We hypothesize that attenuating PACS1 binding of GGA3 also gives rise to a disorder with features overlapping those of PACS1-NDD. This observation better delineates the mechanism by which PACS1 variation predisposes to syndromic intellectual disability.

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“…61 The observation of increased network burst duration and decreased synchrony in our system could be related to patient EEG reports (though rare and variable) for both PACS1 syndrome and a strikingly similar PACS2 syndrome of "excess discontinuity", "generalized slowing", and "slow wave bursts". [62][63][64] However, these are very different systems, and it is possible that variable firing patterns in neurons initiate epileptic activity but are not reflected in EEG recordings. Further experiments with more diverse systems would be needed to fully make this connection.…”

Section: Discussionmentioning

confidence: 99%

iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity

Rylaarsdam

Guemez‐Gamboa

2022

Preprint

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PACS1 syndrome is a neurodevelopmental disorder characterized by intellectual disability and craniofacial abnormalities resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). PACS1 is known to play roles in both the endosomal pathway and nucleus, but little is known about how this variant affects the developing nervous system and patients have few therapeutic options. Here, we used stem cell-derived forebrain organoids to show that PACS1(+/R203W) cells share convergent molecular features of autism spectrum disorder (ASD) through a gain-of-function mechanism. These features include an aberrant propensity towards GABAergic differentiation, increased inhibitory synaptic density, and impaired expression of an ASD-specific gene network enriched at synapses. This work is the first to investigate the impact of the p.R203W variant on the developing brain and suggests a therapy that either clears p.R203W PACS1 or targets convergent pathological mechanisms of ASD could be beneficial for patients.

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Expanding the clinical spectrum associated with the PACS1 p.Arg203Trp mutational hot‐spot: Two additional Italian patients

Cited by 4 publications

References 12 publications

iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity

iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity

Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?

iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity

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