ArticleThe Journal of clinical investigation2015
B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers, 2 of them syntheses that pooled it.
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Who cites it
79 citing papers in PubMed, 2 syntheses or guidelines pooled it, 123 citations in OpenAlex.
- Clinical and Molecular Spectrum ofGenes · 2025Pooled it
- Prenatal Characterization of Houge-Janssens Syndrome Type 2: A Case Report and Systematic Review of Fetal Phenotypes Associated With PPP2R1A Mutations.Molecular genetics & genomic medicine · 2025Pooled it
- A Novel Missense Variant in the GeneBioMed research international · 2021Trial
- A case report of a novelFrontiers in psychiatry · 2026Article
- Cognitive Function and Proteomic Changes in Patients with Autoantibody-Positive Neurodegenerative Dementia.Neurology and therapy · 2025Article
- Jordan syndrome due toTranslational pediatrics · 2025Article
- A Practical Guide to Transition State Analysis in Biomolecular Simulations with TS-DAR.The journal of physical chemistry. B · 2025Article
- Houge-Janssens syndrome.European journal of human genetics : EJHG · 2025Review
- Ppp2r1a haploinsufficiency increases excitatory synaptic transmission and decreases spatial learning by impairing endocannabinoid signaling.The Journal of clinical investigation · 2025Article
- The Prenatal Neuro-Radiological Phenotype Associated With a Recurrent Pathogenic Variant in PPP2R1A.Prenatal diagnosis · 2025Article
- Germline mutations in PPP2R1B in patients with a personal and family history of cancer.JCI insight · 2025Article
- Proteome-wide assessment of differential missense variant clustering in neurodevelopmental disorders and cancer.Cell genomics · 2025Article
- Combining cryo-electron microscopy (cryo-EM) with orthogonal solution state methods to define the molecular basis of the phosphoprotein phosphatase family regulation and substrate specificity.Current opinion in structural biology · 2025Review
- Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum.American journal of human genetics · 2025Article
- De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias.Human molecular genetics · 2025Article
- A de novo missense mutation in PPP2R5D alters dopamine pathways and morphology of iPSC-derived midbrain neurons.Stem cells (Dayton, Ohio) · 2025Article
- Mechanisms of brain overgrowth in autism spectrum disorder with macrocephaly.Frontiers in neuroscience · 2025Review
- Article
- The molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development.Genes & diseases · 2024Review
- Thirteen New Patients ofChildren (Basel, Switzerland) · 2024Article
19 more citing papers are in PubMed but not listed here.
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Authors and funding
28 authors at 16 institutions in 6 countries.
Funding
Abstract
Here we report inherited dysregulation of protein phosphatase activity as a cause of intellectual disability (ID). De novo missense mutations in 2 subunits of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) were identified in 16 individuals with mild to severe ID, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. PP2A comprises catalytic (C), scaffolding (A), and regulatory (B) subunits that determine subcellular anchoring, substrate specificity, and physiological function. Ten patients had mutations within a highly conserved acidic loop of the PPP2R5D-encoded B56δ regulatory subunit, with the same E198K mutation present in 6 individuals. Five patients had mutations in the PPP2R1A-encoded scaffolding Aα subunit, with the same R182W mutation in 3 individuals. Some Aα cases presented with large ventricles, causing macrocephaly and hydrocephalus suspicion, and all cases exhibited partial or complete corpus callosum agenesis. Functional evaluation revealed that mutant A and B subunits were stable and uncoupled from phosphatase activity. Mutant B56δ was A and C binding-deficient, while mutant Aα subunits bound B56δ well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56δ-anchored substrates. Moreover, mutant subunit overexpression resulted in hyperphosphorylation of GSK3β, a B56δ-regulated substrate. This effect was in line with clinical observations, supporting a correlation between the ID degree and biochemical disturbance.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.