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

doi:10.1007/s10048-015-0466-9

. 2016 Jan;17(1):43-9.

doi: 10.1007/s10048-015-0466-9. Epub 2015 Nov 17.

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

Linshan Shang¹, Lindsay B Henderson², Megan T Cho², Donald S Petrey³, Chin-To Fong⁴, Katrina M Haude⁴, Natasha Shur⁵, Julie Lundberg⁵, Natalie Hauser⁶, Jason Carmichael⁶, Jeffrey Innis^{7

8}, Jane Schuette^{7

8}, Yvonne W Wu⁹, Shailesh Asaikar¹⁰, Margaret Pearson¹¹, Leandra Folk², Kyle Retterer², Kristin G Monaghan², Wendy K Chung^{12

13}

Affiliations

¹ Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
² GeneDx, Gaithersburg, MD, USA.
³ Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY, USA.
⁴ University of Rochester Medical Center, Rochester, NY, USA.
⁵ Albany Medical Center, Albany, NY, USA.
⁶ Valley Children's Hospital, Madera, CA, USA.
⁷ Division of Pediatric Genetics, University of Michigan Health System, Ann Arbor, MI, USA.
⁸ Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
⁹ Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Child and Adolescent Neurology Consultants, Sacramento, CA, USA.
¹¹ District Medical Group, Scottsdale, AZ, USA.
¹² Department of Pediatrics, Columbia University Medical Center, New York, NY, USA. wkc15@cumc.columbia.edu.
¹³ Department of Medicine, Columbia University Medical Center, New York, NY, USA. wkc15@cumc.columbia.edu.

PMID: 26576547
PMCID: PMC4765493
DOI: 10.1007/s10048-015-0466-9

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

Linshan Shang et al. Neurogenetics. 2016 Jan.

. 2016 Jan;17(1):43-9.

doi: 10.1007/s10048-015-0466-9. Epub 2015 Nov 17.

Authors

Affiliations

¹ Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
² GeneDx, Gaithersburg, MD, USA.
³ Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY, USA.
⁴ University of Rochester Medical Center, Rochester, NY, USA.
⁵ Albany Medical Center, Albany, NY, USA.
⁶ Valley Children's Hospital, Madera, CA, USA.
⁷ Division of Pediatric Genetics, University of Michigan Health System, Ann Arbor, MI, USA.
⁸ Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
⁹ Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Child and Adolescent Neurology Consultants, Sacramento, CA, USA.
¹¹ District Medical Group, Scottsdale, AZ, USA.
¹² Department of Pediatrics, Columbia University Medical Center, New York, NY, USA. wkc15@cumc.columbia.edu.
¹³ Department of Medicine, Columbia University Medical Center, New York, NY, USA. wkc15@cumc.columbia.edu.

PMID: 26576547
PMCID: PMC4765493
DOI: 10.1007/s10048-015-0466-9

Abstract

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 glycogen synthase kinase 3 beta (GSK3β)-mediated cell growth, chromatin remodeling, and gene transcriptional regulation. Using whole-exome sequencing (WES), we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with intellectual disability (ID) and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures, and dysmorphic features. Among the four variants, 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 subunit binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID.

Keywords: Autism spectrum disorder; De novo mutations; Intellectual disabilities; PPP2R5D; Protein phosphatase; Whole-exome sequencing.

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Figures

**Figure 1. Facial characteristics of individuals with *PPP2R5D* variants**
A. Individual 1, B. Individual 3, C. Individual 7

**Figure 2. Effects of E420K mutation in PPP2R5D**
Both panels show the molecular surfaces of the regulatory and catalytic subunit of PPP2R5D, calculated from homology models (see Methods). The surface of the catalytic subunit is colored green. The surface of the regulatory subunit is colored according to electrostatic potential with red regions indicating electronegative regions and blue indicating electropositive regions. Panel A shows the surface of the wild-type regulatory subunit, and Panel B shows the surface of the E420K mutant. The active site cavity of the catalytic subunit is labeled with a “C”

See this image and copyright information in PMC

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References

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[1] Vissers LE, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, del Rosario M, van Bon BW, Hoischen A, de Vries BB, Brunner HG, Veltman JA. A de novo paradigm for mental retardation. Nature genetics. 2010;42(12):1109–1112. doi:10.1038/ng.712. - PubMed

[2] Vissers LE, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, del Rosario M, van Bon BW, Hoischen A, de Vries BB, Brunner HG, Veltman JA. A de novo paradigm for mental retardation. Nature genetics. 2010;42(12):1109–1112. doi:10.1038/ng.712. - PubMed

[3] Ku CS, Polychronakos C, Tan EK, Naidoo N, Pawitan Y, Roukos DH, Mort M, Cooper DN. A new paradigm emerges from the study of de novo mutations in the context of neurodevelopmental disease. Molecular psychiatry. 2013;18(2):141–153. doi:10.1038/mp.2012.58. - PubMed

[4] Ku CS, Polychronakos C, Tan EK, Naidoo N, Pawitan Y, Roukos DH, Mort M, Cooper DN. A new paradigm emerges from the study of de novo mutations in the context of neurodevelopmental disease. Molecular psychiatry. 2013;18(2):141–153. doi:10.1038/mp.2012.58. - PubMed

[5] Depaoli-Roach AA, Park IK, Cerovsky V, Csortos C, Durbin SD, Kuntz MJ, Sitikov A, Tang PM, Verin A, Zolnierowicz S. Serine/threonine protein phosphatases in the control of cell function. Advances in enzyme regulation. 1994;34:199–224. - PubMed

[6] Depaoli-Roach AA, Park IK, Cerovsky V, Csortos C, Durbin SD, Kuntz MJ, Sitikov A, Tang PM, Verin A, Zolnierowicz S. Serine/threonine protein phosphatases in the control of cell function. Advances in enzyme regulation. 1994;34:199–224. - PubMed

[7] Kiely M, Kiely PA. PP2A: The Wolf in Sheep's Clothing? Cancers. 2015;7(2):648–669. doi:10.3390/cancers7020648. - PMC - PubMed

[8] Kiely M, Kiely PA. PP2A: The Wolf in Sheep's Clothing? Cancers. 2015;7(2):648–669. doi:10.3390/cancers7020648. - PMC - PubMed

[9] Gipson TT, Johnston MV. Plasticity and mTOR: towards restoration of impaired synaptic plasticity in mTOR-related neurogenetic disorders. Neural plasticity. 2012;2012:486402. doi:10.1155/2012/486402. - PMC - PubMed

[10] Gipson TT, Johnston MV. Plasticity and mTOR: towards restoration of impaired synaptic plasticity in mTOR-related neurogenetic disorders. Neural plasticity. 2012;2012:486402. doi:10.1155/2012/486402. - PMC - PubMed

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

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

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