Mutations in the PP2A regulatory subunit B family genes PPP2R5B,PPP2R5C and PPP2R5D cause human overgrowth

Loveday, Chey; Tatton-Brown, Katrina; Clarke, Matthew; Westwood, Isaac; Renwick, Anthony; Ramsay, Emma; Nemeth, Andrea; Campbell, Jennifer; Joss, Shelagh; Gardner, McKinlay; Zachariou, Anna; Elliott, Anna; Ruark, Elise; van Montfort, Rob; The Childhood Overgrowth Collaboration; Rahman, Nazneen

doi:10.1093/hmg/ddv182

Cited by 87Genomics and Rare DiseasesGenetics and Neurodevelopmental DisordersProtein Tyrosine Phosphatases

Mutations in the PP2A regulatory subunit B family genes PPP2R5B,PPP2R5C and PPP2R5D cause human overgrowth

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Loveday, Chey, Tatton-Brown, Katrina, Clarke, Matthew, Westwood, Isaac, Renwick, Anthony, Ramsay, Emma, Nemeth, Andrea, Campbell, Jennifer +8 more·2015·Human Molecular Genetics

DOI 10.1093/hmg/ddv182PMC PMC4527483

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Abstract

Overgrowth syndromes comprise a group of heterogeneous disorders characterised by excessive growth parameters, often in association with intellectual disability. To identify new causes of human overgrowth, we have been undertaking trio-based exome sequencing studies in overgrowth patients and their unaffected parents. Prioritisation of functionally relevant genes with multiple unique de novo mutations revealed four mutations in protein phosphatase 2A (PP2A) regulatory subunit B family genes protein phosphatase 2, regulatory Subunit B', beta (PPP2R5B); protein phosphatase 2, regulatory Subunit B', gamma (PPP2R5C); and protein phosphatase 2, regulatory Subunit B', delta (PPP2R5D). This observation in 3 related genes in 111 individuals with a similar phenotype is greatly in excess of the expected number, as determined from gene-specific de novo mutation rates (P = 1.43 × 10(-10)). Analysis of exome-sequencing data from a follow-up series of overgrowth probands identified a further pathogenic mutation, bringing the total number of affected individuals to 5. Heterozygotes shared similar phenotypic features including increased height, increased head circumference and intellectual disability. The mutations clustered within a region of nine amino acid residues in the aligned protein sequences (P = 1.6 × 10(-5)). We mapped the mutations onto the crystal structure of the PP2A holoenzyme complex to predict their molecular and functional consequences. These studies suggest that the mutations may affect substrate binding, thus perturbing the ability of PP2A to dephosphorylate particular protein substrates. PP2A is a major negative regulator of v-akt murine thymoma viral oncogene homolog 1 (AKT). Thus, our data further expand the list of genes encoding components of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signalling cascade that are disrupted in human overgrowth conditions.

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Mutations in PP2A/B56 family genes correlate with childhood overgrowth and intellectual disability in five individuals.
“It has been reported that mutations of PP2A/B56 family genes correlate with childhood overgrowth and intellectual disability in 5 individuals (Loveday et al., 2015).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Loveday et al., 2015

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Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human
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Authors: Loveday, C., Tatton-Brown, K., Clarke, M., Westwood, I., Renwick, A., Ramsay, E., Nemeth, A., Campbell, J., Joss, S., Gardner, M., Zachariou, A., Elliott, A., Ruark, E., van Montfort, R., The Childhood Overgrowth Collaboration, & Rahman, N.
Affiliations: Institute of Cancer Research (GB)
Churchill Hospital (GB)
Centre for Life (GB)
Chapel Allerton Hospital (GB)
Wellington Hospital (NZ)
Royal Marsden Hospital (GB)
Corresponding author: Rahman, Nazneen
ORCID: Loveday, Chey
Clarke, Matthew
Nemeth, Andrea
Joss, Shelagh
Zachariou, Anna
Ruark, Elise
Rahman, Nazneen
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2015-05-13
Volume: 24
Issue: 17
Pages: 4775-4779
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/ddv182
PMC: PMC4527483
OpenAlex: W2112032347
Cited by: 87
References: 14
Citations by year: 2026: 2 · 2025: 8 · 2024: 8 · 2023: 10 · 2022: 10 · 2021: 12 · 2020: 10 · 2019: 3 · 2018: 9 · 2017: 4 · 2016: 6 · 2015: 5
FWCI: 5.50
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
Locations: Human Molecular Genetics (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Pure Amsterdam UMC (publishedVersion, other-oa)
ePrints Soton (University of Southampton) (acceptedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
Research Portal (King's College London) (submittedVersion)
Funders: Wellcome Trust (098498, 100210, G1001799, 100210/Z/12/Z, WT095219MA, 100210/Z/12/Z.I.W)
Cancer Research UK (C309/A11566, 11566, A11566)
National Institute for Health and Care Research
Medical Research Council (MR/N01104X/1, WT095219MA, G1001799)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords: overgrowth syndromes, PPP2R5C, PPP2R5D, protein phosphatase 2A, de novo mutations, intellectual disability, Akt signaling, PI3K/Akt signaling, substrate binding
MeSH terms: Growth Disorders, Humans, Membrane Proteins, Models, Molecular, Mutation, Phenotype, Protein Conformation, Protein Phosphatase 2, Genetic Association Studies, Exome

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Mutations in the PP2A regulatory subunit B family genes PPP2R5B,PPP2R5C and PPP2R5D cause human overgrowth

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