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

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• 作者：Linshan Shang ; Lindsay B. Henderson ; Megan T. Cho ; Donald S. Petrey…
• 关键词：PPP2R5D ; Intellectual disabilities ; Whole ; exome sequencing ; De novo mutations ; Protein phosphatase ; Autism spectrum disorder
• 刊名：neurogenetics
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：17
• 期：1
• 页码：43-49
• 全文大小：1,330 KB
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• 作者单位：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)
  
  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 Medicine, Columbia University Medical Center, New York, NY, USA
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Neurosciences
  Human Genetics
  Molecular Medicine
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1364-6753

文摘

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