title: B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability.
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.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Houge
authors.forename: Dorien
authors.initials: D
authors.lastname: Haesen
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Sarju
authors.initials: S
authors.lastname: Mehta
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parker
authors.forename: Michael
authors.initials: M
authors.lastname: Wright
authors.forename: Julie
authors.initials: J
authors.lastname: Vogt
authors.forename: Shane
authors.initials: S
authors.lastname: McKee
authors.forename: John L
authors.initials: JL
authors.lastname: Tolmie
authors.forename: Nuno
authors.initials: N
authors.lastname: Cordeiro
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.forename: Margot R F
authors.initials: MR
authors.lastname: Reijnders
authors.forename: Siren
authors.initials: S
authors.lastname: Berland
authors.forename: Eli
authors.initials: E
authors.lastname: Hayman
authors.forename: Eli
authors.initials: E
authors.lastname: Lahat
authors.forename: Eva H
authors.initials: EH
authors.lastname: Brilstra
authors.forename: Koen L I
authors.initials: KL
authors.lastname: van Gassen
authors.forename: Evelien
authors.initials: E
authors.lastname: Zonneveld-Huijssoon
authors.forename: Charlotte I
authors.initials: CI
authors.lastname: de Bie
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.forename: Rita
authors.initials: R
authors.lastname: Holdhus
authors.forename: Vidar M
authors.initials: VM
authors.lastname: Steen
authors.forename: Stein Ove
authors.initials: SO
authors.lastname: Døskeland
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
authors.forename: Veerle
authors.initials: V
authors.lastname: Janssens
mesh_terms: D000293:Adolescent; D000328:Adult; D061085:Agenesis of Corpus Callosum / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D003337:Corpus Callosum / Q000201:enzymology / Q000473:pathology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007223:Infant; D008297:Male; D001523:Mental Disorders / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D020125:Mutation, Missense; D010766:Phosphorylation / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: C525691:PPP2R5D protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2