Protein Phosphatase 2A (PP2A) mutations in brain function, development, and neurologic disease

Verbinnen, Iris; Vaneynde, Pieter; Reynhout, Sara; Lenaerts, Liesbeth; Derua, Rita; Houge, Gunnar; Janssens, Veerle

doi:10.1042/bst20201313

Cited by 25 publications

(27 citation statements)

References 119 publications

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“…Thus far, most PP2A research has been performed in a cancer-context, where the large majority of PP2A trimers act as tumour suppressors ( Meeusen and Janssens, 2018 ; Remmerie and Janssens, 2019 ). Since 2015, however, de novo mutations in several PP2A genes have been implicated as causative for neurodevelopmental or other inborn brain disorders ( Houge et al, 2015 ; Loveday et al, 2015 ; Sandal et al, 2021 ; Verbinnen et al, 2021 ), while some inherited mutations in other PP2A genes mainly affected development of other organs ( Guran et al, 2019 ). Specifically, PP2A-related neurodevelopmental disorders are characterized by mutations in PPP2R1A (Aα), PPP2CA (Cα), PPP2R2C (B55γ), PPP2R5B (B56β) , PPP2R5C (B56γ) , and PPP2R5D (B56δ), with most patients and mutations, so far, found in PPP2R5D ( Figures 3A–C ).…”

Section: Ser/thr Phosphatases In Congenital Diseasesmentioning

confidence: 99%

“…PP2A A- and C-subunit expression is high in both developing and adult brain tissue, with a higher expression of PPP2R1A and PPP2CA as compared with their β isoform encoding genes, PPP2R1B and PPP2CB ( Verbinnen et al, 2021 ). As such, PP2A has been shown to be important in brain development and function, with several mouse studies performed ( Reynhout and Janssens, 2019 ; Verbinnen et al, 2021 ). Brain-specific PP2A Cα knockout in mice has been linked to microcephaly and cortical atrophy, while learning and memory was also impaired ( Liu et al, 2018 ).…”

Section: Ser/thr Phosphatases In Congenital Diseasesmentioning

confidence: 99%

“…One variant (p.Ser152Phe) did not show any PP2A subunit binding defects but caused a reduced number in spikes upon expression in primary mouse neurons, and was associated with a very mild phenotype (autism spectrum disorder but no intellectual disability) ( Lenaerts et al, 2021 ). Thus, the wide variability of B-subunit binding defects could explain the diversity in clinical manifestations and could also confer different pathogenic mechanisms or even a combination of different mechanisms such as losses- and gains-of-function of specific PP2A holoenzymes ( Verbinnen et al, 2021 ). Of note is the association between somatic PPP2R1A variants with several cancers, such as endometrial cancer and lung cancer ( Remmerie and Janssens, 2019 ), and with some of these variants being identical to those found in the severely affected PPP2R1A subgroup of neurodevelopmental disorders.…”

Section: Ser/thr Phosphatases In Congenital Diseasesmentioning

confidence: 99%

“…PPP2R5D is highly expressed during embryogenesis and in the adult brain, indicating its important role ( Verbinnen et al, 2021 ). During embryogenesis, it plays a role in the cell cycle, being a negative regulator of CDC25 phosphatase by targeting PP2A to the nucleus ( Biswas et al, 2020 ).…”

Section: Ser/thr Phosphatases In Congenital Diseasesmentioning

confidence: 99%

“…frontal bossing) and less common symptoms, such as epilepsy, autism spectrum disorder, ADHD and early-onset Parkinsonism ( Houge et al, 2015 ; Loveday et al, 2015 ; Shang et al, 2016 ; Yeung et al, 2017 ; Mirzaa et al, 2019 ; Kim et al, 2020 ; Hetzelt et al, 2021 ; Walker et al, 2021 ; Yan et al, 2021 ; Oyama et al, 2022 ) (OMIM# 616355 ). Thus far, seventeen variants have been reported for PPP2R5D which are spread throughout the whole protein, but some seem to cluster around a conserved acidic loop, or a canonical short linear interaction motif-binding site ( Figure 3C ) ( Verbinnen et al, 2021 ). Current literature states that these de novo variants act in a dominant-negative fashion, showing decrease in both A- and C-subunit binding, thus potentially trapping the substrate ( Houge et al, 2015 ).…”

Section: Ser/thr Phosphatases In Congenital Diseasesmentioning

confidence: 99%

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The role of serine/threonine phosphatases in human development: Evidence from congenital disorders

Vaneynde

Verbinnen²,

Janssens³

2022

Front. Cell Dev. Biol.

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Reversible protein phosphorylation is a fundamental regulation mechanism in eukaryotic cell and organismal physiology, and in human health and disease. Until recently, and unlike protein kinases, mutations in serine/threonine protein phosphatases (PSP) had not been commonly associated with disorders of human development. Here, we have summarized the current knowledge on congenital diseases caused by mutations, inherited or de novo, in one of 38 human PSP genes, encoding a monomeric phosphatase or a catalytic subunit of a multimeric phosphatase. In addition, we highlight similar pathogenic mutations in genes encoding a specific regulatory subunit of a multimeric PSP. Overall, we describe 19 affected genes, and find that most pathogenic variants are loss-of-function, with just a few examples of gain-of-function alterations. Moreover, despite their widespread tissue expression, the large majority of congenital PSP disorders are characterised by brain-specific abnormalities, suggesting a generalized, major role for PSPs in brain development and function. However, even if the pathogenic mechanisms are relatively well understood for a small number of PSP disorders, this knowledge is still incomplete for most of them, and the further identification of downstream targets and effectors of the affected PSPs is eagerly awaited through studies in appropriate in vitro and in vivo disease models. Such lacking studies could elucidate the exact mechanisms through which these diseases act, and possibly open up new therapeutic avenues.

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Section: Ser/thr Phosphatases In Congenital Diseasesmentioning

confidence: 99%

Section: Ser/thr Phosphatases In Congenital Diseasesmentioning

confidence: 99%

Section: Ser/thr Phosphatases In Congenital Diseasesmentioning

confidence: 99%

Section: Ser/thr Phosphatases In Congenital Diseasesmentioning

confidence: 99%

Section: Ser/thr Phosphatases In Congenital Diseasesmentioning

confidence: 99%

See 3 more Smart Citations

The role of serine/threonine phosphatases in human development: Evidence from congenital disorders

Vaneynde

Verbinnen²,

Janssens³

2022

Front. Cell Dev. Biol.

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An in‐frame deletion affecting the critical acid loop of PPP2R5D is associated with a neonatal lethal form of PPP2R5D‐related neurodevelopmental disorder

Alhajaj

Lacroix

Trakadis

et al. 2023

American J of Med Genetics Pt A

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Heterozygous pathogenic variants in PPP2R5D gene are associated with PPP2R5D‐related neurodevelopmental disorder, a rare autosomal dominant condition, characterized by neurodevelopmental impairment in childhood, macrocephaly/megalencephaly, hypotonia, epilepsy, and dysmorphic features. Up‐to‐date, only approximately 100 cases have been published in the literature and the full phenotypic and genotypic spectrum have not yet been fully described. PPP2R5D gene encodes the B56δ subunit of the PP2A enzyme complex. We describe a neonatal form of PPP2R5D‐related disorder with early infantile death, caused by a novel in‐frame deletion causing loss of 8 amino acids and insertion of serine at position 201 (p.Phe194_Pro201delinsSer) of the B56δ subunit. This deletion is predicted to disrupt a critical acidic loop of amino acids important for binding other subunits of the PP2A enzyme complex, and harbors many of the residues previously reported to cause a mild–moderate form of this condition. This report describes a neonatal lethal presentation of the PPP2R5D‐related neurodevelopmental disorder and provides additional evidence that disruption of the acidic loop is an important pathomechanism underlying PPP2R5D‐related disorder.

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Cross‐Ethnic Variant Screening and Burden Analysis of PTPA in Parkinson's Disease

Lin

Jiang

et al. 2023

Movement Disorders

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Background: Recently, homozygous variants in PTPA were identified as the disease cause for two pedigrees with early-onset parkinsonism and intellectual disability. Although the initial link between PTPA and parkinsonism has been established, further replication was still necessary. Objectives: To evaluate the genetic role of PTPA in Parkinson's disease (PD).Methods: We analyzed rare variants of PTPA in cohorts of Asian and European ancestries (N case = 2743, N control = 8177) with whole-exome sequencing, and further explored the functional effect of the target variant. Results: One patient with early-onset PD from a consanguineous family carried the homozygous variant p.Met329Val, while her parents and elder sister with heterozygous p.Met329Val were healthy. This patient developed minor cognitive decline within 1 year, with a Montreal Cognitive Assessment (MoCA) score dropping from 28 to 25. Functional exploration with overexpression studies suggested that this variant was associated with decreased protein phosphatase 2A (PTPA) protein level by affecting protein stability, but not mRNA expression. Conclusions: These results have broadened the mutation spectrum of PTPA, and paved the way for further research into the role of PTPA in PD.

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Protein Phosphatase 2A (PP2A) mutations in brain function, development, and neurologic disease

Cited by 25 publications

References 119 publications

The role of serine/threonine phosphatases in human development: Evidence from congenital disorders

The role of serine/threonine phosphatases in human development: Evidence from congenital disorders

An in‐frame deletion affecting the critical acid loop of PPP2R5D is associated with a neonatal lethal form of PPP2R5D‐related neurodevelopmental disorder

Cross‐Ethnic Variant Screening and Burden Analysis of PTPA in Parkinson's Disease

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