Journal article
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, Vol.34(2), pp.193-203
01/29/2025
DOI: 10.1093/hmg/ddae166
PMCID: PMC11780858
PMID: 39565297
Appears in UI Libraries Support Open Access
Abstract
Abstract 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.
Details
- Title: Subtitle
- De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias
- Creators
- Priyanka Sandal - University of IowaChian Ju Jong - University of IowaRonald A Merrill - University of IowaGrace J Kollman - University of IowaAustin H Paden - University of Iowa, Stead Family Department of PediatricsEric G Bend - Exact SciencesJennifer Sullivan - University of North Carolina at Chapel HillRebecca C Spillmann - Duke Medical CenterVandana Shashi - Duke Medical CenterAnneke T Vulto-van Silfhout - Maastricht University Medical CentreRolph Pfundt - Radboud Institute for Molecular Life SciencesBert B A de Vries - Radboud Institute for Molecular Life SciencesPan P Li - Johns Hopkins MedicineLouise S Bicknell - University of OtagoStefan Strack - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.34(2), pp.193-203
- DOI
- 10.1093/hmg/ddae166
- PMID
- 39565297
- PMCID
- PMC11780858
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Publisher
- Oxford University Press
- Grant note
We would like to acknowledge Ms Yufang Kong for technical assistance with subcloning and site-directed mutagenesis. The data used for Supplemental Fig. S2C were obtained from the GTEx Portal on 6/5/24. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.
- Language
- English
- Electronic publication date
- 11/20/2024
- Date published
- 01/29/2025
- Academic Unit
- Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
- Record Identifier
- 9984749496702771
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