{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:01:27Z","timestamp":1791925287095,"version":"4.3.4"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T00:00:00Z","timestamp":1732060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R21 AG080472-01"],"award-info":[{"award-number":["R21 AG080472-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ataxia Charlevoix-Saguenay Foundation"},{"DOI":"10.13039\/100014370","name":"Simons Foundation Autism Research Initiative","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014370","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The heterotrimeric protein phosphatase 2A (PP2A) complex catalyzes about half of Ser\/Thr dephosphorylations in eukaryotic cells. A CAG repeat expansion in the neuron-specific protein PP2A regulatory subunit PPP2R2B gene causes spinocerebellar ataxia type 12 (SCA12). We established five monoallelic missense variants in PPP2R2B (four confirmed as de novo) as a cause of intellectual disability with developmental delay (R149P, T246K, N310K, E37K, I427T). In addition to moderate to severe intellectual disability and developmental delay, affected individuals presented with seizures, microcephaly, aggression, hypotonia, as well as broad-based or stiff gait. We used biochemical and cellular assays, including a novel luciferase complementation assay to interrogate PP2A holoenzyme assembly and activity, as well as deregulated mitochondrial dynamics as possible pathogenic mechanisms. Cell-based assays documented impaired ability of PPP2R2B missense variants to incorporate into the PP2A holoenzyme, localize to mitochondria, induce fission of neuronal mitochondria, and dephosphorylate the mitochondrial fission enzyme dynamin-related protein 1. AlphaMissense-based pathogenicity prediction suggested that an additional seven unreported missense variants may be pathogenic. In conclusion, our studies identify loss-of-function at the PPP2R2B locus as the basis for syndromic intellectual disability with developmental delay. They also extend PPP2R2B-related pathologies from neurodegenerative (SCA12) to neurodevelopmental disorders and suggests that altered mitochondrial dynamics may contribute to mechanisms.<\/jats:p>","DOI":"10.1093\/hmg\/ddae166","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T15:15:33Z","timestamp":1732115733000},"page":"193-203","source":"Crossref","is-referenced-by-count":10,"title":["<i>De novo<\/i> missense variants in the PP2A regulatory subunit <i>PPP2R2B<\/i> in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias"],"prefix":"10.1093","volume":"34","author":[{"given":"Priyanka","family":"Sandal","sequence":"first","affiliation":[{"name":"Department of Neuroscience and Pharmacology, University of Iowa, Carver College of Medicine , Bowen Science Building, 51 Newton Road, Iowa City, IA 52242 ,","place":["United States"]},{"name":"Biologics Discovery, Abbott Laboratories , 100 Abbott Park Road, Abbott Park, IL 60064 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chian Ju","family":"Jong","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Pharmacology, University of Iowa, Carver College of Medicine , Bowen Science Building, 51 Newton Road, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald A","family":"Merrill","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Pharmacology, University of Iowa, Carver College of Medicine , Bowen Science Building, 51 Newton Road, Iowa City, IA 52242 ,","place":["United States"]},{"name":"Department of Molecular Physiology and Biophysics, University of Iowa, Carver College of Medicine , Bowen Science Building, 51 Newton Road, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace J","family":"Kollman","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Pharmacology, University of Iowa, Carver College of Medicine , Bowen Science Building, 51 Newton Road, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin H","family":"Paden","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Pharmacology, University of Iowa, Carver College of Medicine , Bowen Science Building, 51 Newton Road, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric G","family":"Bend","sequence":"additional","affiliation":[{"name":"PreventionGenetics, Part of Exact Sciences , 3800 S Business Park Ave, Marshfield, WI 54449 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of North Carolina Chapel Hill , 260 MacNider Hall, CB# 7220, 333 South Columbia St., Chapel Hill, NC 27599-7220 ,","place":["United States"]},{"name":"Department of Pediatrics - Medical Genetics, Duke University Medical Center , DUMC Box 103857, Durham, NC 27710 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca C","family":"Spillmann","sequence":"additional","affiliation":[{"name":"Department of Pediatrics - Medical Genetics, Duke University Medical Center , DUMC Box 103857, Durham, NC 27710 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandana","family":"Shashi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics - Medical Genetics, Duke University Medical Center , DUMC Box 103857, Durham, NC 27710 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke T","family":"Vulto-van Silfhout","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Maastricht University Medical Center , P. Debyelaan 25, Maastricht 6229 HX ,","place":["the Netherlands"]},{"name":"Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Medical Centre Department . of Human Genetics, , Geert Grooteplein Zuid 10, Nijmegen 6525 GA ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolph","family":"Pfundt","sequence":"additional","affiliation":[{"name":"Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Medical Centre Department . of Human Genetics, , Geert Grooteplein Zuid 10, Nijmegen 6525 GA ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert B A","family":"de Vries","sequence":"additional","affiliation":[{"name":"Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Medical Centre Department . of Human Genetics, , Geert Grooteplein Zuid 10, Nijmegen 6525 GA ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan P","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Neurobiology , Department of Psychiatry and Behavioral Sciences, , 600 N Wolfe St, CMSC 8-117, Baltimore, MD 21287 ,","place":["United States"]},{"name":"Johns Hopkins University School of Medicine , Department of Psychiatry and Behavioral Sciences, , 600 N Wolfe St, CMSC 8-117, Baltimore, MD 21287 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6899-9322","authenticated-orcid":false,"given":"Louise S","family":"Bicknell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Otago , 710 Cumberland St., Dunedin North, Dunedin 9016 ,","place":["New 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