{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:40:52Z","timestamp":1787805652578,"version":"build-2784847793"},"reference-count":61,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,2,14]],"date-time":"2020-02-14T00:00:00Z","timestamp":1581638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Protein Phosphatase 2 Regulatory Subunit B\u2032 Delta (PPP2R5D)-related intellectual disability (ID) and neurodevelopmental delay results from germline de novo mutations in the PPP2R5D gene. This gene encodes the protein PPP2R5D (also known as the B56 delta subunit), which is an isoform of the subunit family B56 of the enzyme serine\/threonine-protein phosphatase 2A (PP2A). Clinical signs include intellectual disability (ID); autism spectrum disorder (ASD); epilepsy; speech problems; behavioral challenges; and ophthalmologic, skeletal, endocrine, cardiac, and genital malformations. The association of defective PP2A activity in the brain with a wide range of severity of ID, along with its role in ASD, Alzheimer\u2019s disease, and Parkinson\u2019s-like symptoms, have recently generated the impetus for further research into mutations within this gene. PP2A, together with protein phosphatase 1 (PP1), accounts for more than 90% of all phospho-serine\/threonine dephosphorylations in different tissues. The specificity for a wide variety of substrates is determined through nearly 100 different PP2A holoenzymes that are formed by at least 23 types of regulatory B subunits, and two isoforms each of the catalytic subunit C and the structural subunit A. In the mammalian brain, PP2A-mediated protein dephosphorylation plays an important role in learning and memory. The PPP2R5D subunit is highly expressed in the brain and the PPP2A\u2013PPP2R5D holoenzyme plays an important role in maintaining neurons and regulating neuronal signaling. From 2015 to 2017, 25 individuals with PPP2R5D-related developmental disorder were diagnosed. Since then, Whole-Exome Sequencing (WES) has helped to identify more unrelated individuals clinically diagnosed with a neurodevelopmental disorder with pathological variants of PPP2R5D. In this review, we discuss the current understanding of the clinical and genetic aspects of the disorder in the context of the known functions of the PP2A\u2013PPP2R5D holoenzyme in the brain, as well as the pathogenic mutations in PPP2R5D that lead to deficient PP2A\u2013PPP2R5D dephosphorylation and their implications during development and in the etiology of autism, Parkinson\u2019s disease, Alzheimer\u2019s disease, and so forth. In the future, tools such as transgenic animals carrying pathogenic PPP2R5D mutations, and patient-derived induced pluripotent stem cell lines need to be developed in order to fully understand the effects of these mutations on different neural cell types.<\/jats:p>","DOI":"10.3390\/ijms21041286","type":"journal-article","created":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T04:06:01Z","timestamp":1582085161000},"page":"1286","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder"],"prefix":"10.3390","volume":"21","author":[{"given":"Dayita","family":"Biswas","sequence":"first","affiliation":[{"name":"SPARK Program Scholar, Institute for Regenerative Cures, University of California, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whitney","family":"Cary","sequence":"additional","affiliation":[{"name":"Stem Cell Program, UC Davis School of Medicine. The University of California, Sacramento, CA 95817, USA"},{"name":"UC Davis Gene Therapy Program, University of California, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan A.","family":"Nolta","sequence":"additional","affiliation":[{"name":"SPARK Program Scholar, Institute for Regenerative Cures, University of California, Sacramento, CA 95817, USA"},{"name":"Stem Cell Program, UC Davis School of Medicine. The University of California, Sacramento, CA 95817, USA"},{"name":"UC Davis Gene Therapy Program, University of California, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1172\/JCI79860","article-title":"B56delta-related protein phosphatase 2A dysfunction identified in patients with intellectual disability","volume":"125","author":"Houge","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4775","DOI":"10.1093\/hmg\/ddv182","article-title":"Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth","volume":"24","author":"Loveday","year":"2015","journal-title":"Hum. Mol. 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