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neurogenetics

, Volume 17, Issue 1, pp 43–49 | Cite as

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

  • Linshan Shang
  • Lindsay B. Henderson
  • Megan T. Cho
  • Donald S. Petrey
  • Chin-To Fong
  • Katrina M. Haude
  • Natasha Shur
  • Julie Lundberg
  • Natalie Hauser
  • Jason Carmichael
  • Jeffrey Innis
  • Jane Schuette
  • Yvonne W. Wu
  • Shailesh Asaikar
  • Margaret Pearson
  • Leandra Folk
  • Kyle Retterer
  • Kristin G. Monaghan
  • Wendy K. ChungEmail author
Original Article

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

PPP2R5D Intellectual disabilities Whole-exome sequencing De novo mutations Protein phosphatase Autism spectrum disorder 

Notes

Acknowledgments

We thank the probands and families for their generous contributions. This work was supported in part by a grant from the Simons Foundation and from the NIH (GM030518).

Compliance with ethical standards

Conflicts of interest

Lindsay Henderson, Megan Cho, Leandra Folk, Kyle Retterer, and Kristin Monaghan are employees of GeneDx.

Wendy Chung is a consultant to BioReference Laboratories.

The other authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Linshan Shang
    • 1
  • Lindsay B. Henderson
    • 2
  • Megan T. Cho
    • 2
  • Donald S. Petrey
    • 3
  • Chin-To Fong
    • 4
  • Katrina M. Haude
    • 4
  • Natasha Shur
    • 5
  • Julie Lundberg
    • 5
  • Natalie Hauser
    • 6
  • Jason Carmichael
    • 6
  • Jeffrey Innis
    • 7
    • 8
  • Jane Schuette
    • 7
    • 8
  • Yvonne W. Wu
    • 9
  • Shailesh Asaikar
    • 10
  • Margaret Pearson
    • 11
  • Leandra Folk
    • 2
  • Kyle Retterer
    • 2
  • Kristin G. Monaghan
    • 2
  • Wendy K. Chung
    • 1
    • 12
    Email author
  1. 1.Department of PediatricsColumbia University Medical CenterNew YorkUSA
  2. 2.GeneDxGaithersburgUSA
  3. 3.Department of Biochemistry and Molecular BiophysicsColumbia University Medical CenterNew YorkUSA
  4. 4.University of Rochester Medical CenterRochesterUSA
  5. 5.Albany Medical CenterAlbanyUSA
  6. 6.Valley Children’s HospitalMaderaUSA
  7. 7.Division of Pediatric GeneticsUniversity of Michigan Health SystemAnn ArborUSA
  8. 8.Department of Human GeneticsUniversity of Michigan Medical SchoolAnn ArborUSA
  9. 9.Departments of Neurology and PediatricsUniversity of California San FranciscoSan FranciscoUSA
  10. 10.Child and Adolescent Neurology ConsultantsSacramentoUSA
  11. 11.District Medical GroupScottsdaleUSA
  12. 12.Department of MedicineColumbia University Medical CenterNew YorkUSA

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