B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability

Houge, Gunnar; Haesen, Dorien; Vissers, Lisenka E.L.M.; Mehta, Sarju G.; Parker, Michael; Wright, Michael J.; Vogt, Julie; McKee, Shane; Tolmie, John; Cordeiro, Nuno; Kleefstra, Tjitske; Willemsen, Marjolein H.; Reijnders, Margot R.F.; Berland, Siren; Hayman, E.; Lahat, Eli; Brilstra, Eva H.; Gassen, Koen van; Zonneveld‐Huijssoon, Evelien; Bie, Charlotte I. de; Hoischen, Alexander; Eichler, Evan E.; Holdhus, Rita; Steen, Vidar M.; Døskeland, Stein Ove; Hurles, Matthew E.; FitzPatrick, David R.; Janssens, Veerle

doi:10.1172/jci79860

Cited by 103 publications

(207 citation statements)

References 48 publications

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“…All four variants change a highly conserved negatively charged glutamic acid (E) residue to positively charged lysine (K) and are predicted to have a pathogenic effect by various algorithms (Table 1). Two of the variants we identified, E198K and E200K, have been reported in previous studiess of developmental disorders, overgrowth, autism, and intellectual disability [13,15-17]. The E197K and the recurrent E420K variant have not been previously reported.…”

Section: Resultsmentioning

confidence: 62%

“…Based on the functional studies of Houge et al, E198K and E200K disrupt the PP2A holoenzyme subunit binding and impair the dephosphorylation of specific substrates [17]. One of the new variants we identified, E197K is also located in the highly-conserved acidic B56δ loop, which is essential for holoenzyme formation.…”

Section: Resultsmentioning

confidence: 99%

“…Variants in the PP2A regulatory subunit B family genes including , PPP2R5B, PPP2R5C and PPP2R5D; as well as its scaffolding Aα subunit PPP2R1A, have recently been reported in association with developmental disorders, ASD, human overgrowth and intellectual disability [13-17]. Two variants we identified, E198K and E200K, were also previously identified in individuals with clinical features including overgrowth, ID, hypospadias and Parkinsonism [15]; and severe, undiagnosed developmental disorders [13], which are also observed in some of the individuals in our study (Table 2).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D; as well as its scaffolding Aα subunit PPP2R1A , have been recently reported to be associated with developmental disorders, autism, overgrowth, and ID [13-17]. In the present study, we performed clinical WES in 2790 individuals with ID and related neurodevelopmental disorders and identified four independent, de novo , predicted pathogenic variants in PPP2R5D in a total of seven individuals.…”

Section: Introductionmentioning

confidence: 96%

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De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism

Shang

Henderson²,

Cho³

et al. 2015

Neurogenetics

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Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and GSK3β-mediated cell growth, chromatin remodeling and gene transcriptional regulation. Using WES, we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with ID and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures and dysmorphic features. Among the four variant, two have been previously reported, and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K), and are predicted to disrupt the PP2A subunits binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID.

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Section: Resultsmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

See 2 more Smart Citations

De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism

Shang

Henderson²,

Cho³

et al. 2015

Neurogenetics

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show abstract

“…Eleven other patients with PP2R5D mutations have been reported and most did not have overgrowth, but 7 patients had macrocephaly. However, the other patients had normal head size or microcephaly [Houge et al, 2015].…”

Section: Ppp2r5b Ppp2r5c and Ppp2r5d-related Overgrowthmentioning

confidence: 93%

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

et al. 2018

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The overgrowth syndromes are important to diagnose, not just for accurate genetic counseling, but also for knowledge surrounding cancer surveillance and prognosis. There has been a recent expansion in the number of genes associated with a mendelian overgrowth phenotype, so this review updates previous classifications of overgrowth syndromes. We also describe a clinical and molecular approach to the investigation of individuals presenting with overgrowth. This review aims to assist the clinical diagnosis of generalized overgrowth syndromes by outlining the salient features of well-known overgrowth syndromes alongside the many syndromes that have been discovered and classified more recently. We provide key clinical “handles” to aid clinical diagnosis and a list of genes to aid with panel design when using next generation sequencing, which we believe is frequently needed due to the overlapping phenotypic features seen between overgrowth syndromes.

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Targeted disruption of the mouse protein phosphatase ppm1l gene leads to structural abnormalities in the brain

et al. 2016

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PPM1L, a member of the metal-dependent protein phosphatase (PPM) family, is involved in regulating the stress-activated protein kinase pathway and ceramide trafficking. However, the physiological function of PPM1L in the brain is unclear. In this study, we generated and analyzed ppm1l-deficient mice in order to investigate PPM1L functions in the brain. Our results indicate that ppm1l is highly expressed in the central nervous system during mouse development and that ppm1l mice display impaired motor performance and morphological abnormalities in the forebrain. Electron microscopic and immunohistochemical analyses suggest that these abnormalities are due to impaired axonal tract formation. Our novel findings suggest an important role for PPM1L in brain development.

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B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability

Cited by 103 publications

References 48 publications

De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism

De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

Targeted disruption of the mouse protein phosphatase ppm1l gene leads to structural abnormalities in the brain

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