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Human Genetics

, Volume 135, Issue 12, pp 1399–1409 | Cite as

De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease

  • Lijiang Ma
  • Yavuz Bayram
  • Heather M. McLaughlin
  • Megan T. Cho
  • Alyson Krokosky
  • Clesson E. Turner
  • Kristin Lindstrom
  • Caleb P. Bupp
  • Katey Mayberry
  • Weiyi Mu
  • Joann Bodurtha
  • Veronique Weinstein
  • Neda Zadeh
  • Wendy Alcaraz
  • Zöe Powis
  • Yunru Shao
  • Daryl A. Scott
  • Andrea M. Lewis
  • Janson J. White
  • Shalani N. Jhangiani
  • Elif Yilmaz Gulec
  • Seema R. Lalani
  • James R. Lupski
  • Kyle Retterer
  • Rhonda E. Schnur
  • Ingrid M. Wentzensen
  • Sherri Bale
  • Wendy K. ChungEmail author
Original Investigation

Abstract

Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta (PPP1CB) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins. The PPP1CB gene encodes a PP1 subunit that regulates the level of protein phosphorylation. All five altered amino acids we observed are highly conserved among the PP1 subunit family, and all are predicted to disrupt PP1 subunit binding and impair dephosphorylation. Our data suggest that our heterozygous de novo PPP1CB pathogenic variants are associated with syndromic intellectual disability.

Keywords

Congenital Heart Disease Intellectual Disability Intellectual Disability Okadaic Acid Missense Variant 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank the patients and their families for their generous participation. This work was supported in part by a grant from the Simons Foundation and from the NIH (GM030518), NINDS (NS058529), and NHGRI/NHLBI (HG006542).

Compliance with ethical standards

Conflict of interest

Heather McLaughlin, Megan Cho, Kyle Retterer, Rhonda Schnur, Ingrid Wentzensen, and Sherri Bale are employees of GeneDx. Wendy Chung is a former employee of GeneDx and a paid consultant for Regeneron Pharmaceuticals. JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc., serves on the Scientific Advisory Board of the Baylor Miraca Genetics Laboratory, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The other authors declare that they have no conflict of interest.

Supplementary material

439_2016_1731_MOESM1_ESM.docx (25 kb)
Supplementary material 1 (DOCX 25 kb)

References

  1. Aggen JB, Nairn AC, Chamberlin R (2000) Regulation of protein phosphatase-1. Chem Biol 7(1):R13–R23CrossRefPubMedGoogle Scholar
  2. Ansai T, Dupuy LC, Barik S (1996) Interactions between a minimal protein serine/threonine phosphatase and its phosphopeptide substrate sequence. J Biol Chem 271(40):24401–24407CrossRefPubMedGoogle Scholar
  3. Bainbridge MN, Wiszniewski W, Murdock DR, Friedman J, Gonzaga-Jauregui C et al (2011) Whole-genome sequencing for optimized patient management. Sci Transl Med 3(87):87re3CrossRefPubMedPubMedCentralGoogle Scholar
  4. Barker HM, Brewis ND, Street AJ, Spurr NK, Cohen PT (1994) Three genes for protein phosphatase 1 map to different human chromosomes: sequence, expression and gene localisation of protein serine/threonine phosphatase 1 beta (PPP1CB). Biochim Biophys Acta 1220(2):212–218CrossRefPubMedGoogle Scholar
  5. Bausen M, Weltzien F, Betz H, O’Sullivan GA (2010) Regulation of postsynaptic gephyrin cluster size by protein phosphatase 1. Mol Cell Neurosci 44:201–209CrossRefPubMedGoogle Scholar
  6. Bianchi M, De LS, Vietri M, Vietri M, Villa-Moruzzi E (2005) Reciprocally interacting domains of protein phosphatase 1 and focal adhesion kinase. Mol Cell Biochem 272:85–90CrossRefPubMedGoogle Scholar
  7. Bordelon JR, Smith Y, Nairn AC, Colbran RJ, Greengard P et al (2005) Differential localization of protein phosphatase-1alpha, beta and gamma1 isoforms in primate prefrontal cortex. Cereb Cortex 15(12):1928–1937CrossRefPubMedPubMedCentralGoogle Scholar
  8. Ceulemans H, Vulsteke V, De Maeyer M, Tatchell K, Stalmans W et al (2002) Binding of the concave surface of the Sds22 superhelix to the alpha 4/alpha 5/alpha 6-triangle of protein phosphatase-1. J Biol Chem 277(49):47331–47337CrossRefPubMedGoogle Scholar
  9. Cohen P, Cohen PT (1989) Protein phosphatases come of age. J Biol Chem 264(36):21435–21438PubMedGoogle Scholar
  10. Cordeddu V, Di Schiavi E, Pennacchio LA, Ma’ayan A, Sarkozy A et al (2009) Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nature Genet 41:1022–1026CrossRefPubMedPubMedCentralGoogle Scholar
  11. Farwell KD, Shahmirzadi L, El-Khechen D, Powis Z, Chao EC et al (2015) Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med 17(7):578–586CrossRefPubMedGoogle Scholar
  12. Flores-Delgado G, Liu CW, Sposto R, Berndt N (2007) A limited screen for protein interactions reveals new roles for protein phosphatase 1 in cell cycle control and apoptosis. J Proteome Res 6(3):1165–1175CrossRefPubMedGoogle Scholar
  13. Genoux D, Haditsch U, Knobloch M, Michalon A, Storm D et al (2002) Protein phosphatase 1 is a molecular constraint on learning and memory. Nature 418(6901):970–975CrossRefPubMedGoogle Scholar
  14. Gibbons JA, Kozubowski L, Tatchell K, Shenolikar S (2007) Expression of human protein phosphatase-1 in Saccharomyces cerevisiae highlights the role of phosphatase isoforms in regulating eukaryotic functions. J Biol Chem 282(30):21838–21847CrossRefPubMedGoogle Scholar
  15. Gräff J, Koshibu K, Jouvenceau A, Dutar P, Mansuy IM (2010) Protein phosphatase 1-dependent transcriptional programs for long-term memory and plasticity. Learn Mem 17(7):355–363CrossRefPubMedGoogle Scholar
  16. Gripp KW, Zand DJ, Demmer L, Anderson CE, Dobyns WB et al (2013) Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis. Am J Med Genet 161A:2420–2430PubMedGoogle Scholar
  17. Gripp KW, Aldinger KA, Bennett JT, Baker L, Tusi J et al (2016) A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair. Am J Med Genet A 170(9):2237–2247CrossRefPubMedGoogle Scholar
  18. Hamdan FF, Srour M, Capo-Chichi JM, Daoud H, Nassif C et al (2014) De novo mutations in moderate or severe intellectual disability. PLoS Genet 10(10):e1004772CrossRefPubMedPubMedCentralGoogle Scholar
  19. He X, Sanders SJ, Liu L, De Rubeis S, Lim ET et al (2013) Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes. PLoS Genet 9(8):e1003671CrossRefPubMedPubMedCentralGoogle Scholar
  20. Hoban R, Roberts AE, Demmer L, Jethva R, Shephard B (2012) Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophic cardiomyopathy in a premature infant. Am J Med Genet 158A:1411–1413CrossRefPubMedGoogle Scholar
  21. Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE et al (2015) De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science 350(6265):1262–1266CrossRefPubMedPubMedCentralGoogle Scholar
  22. Iacobazzi D, Garaeva I, Albertario A, Cherif M, Angelini GD et al (2015) Protein Phosphatase 1 Beta is Modulated by Chronic Hypoxia and Involved in the Angiogenic Endothelial Cell Migration. Cell Physiol Biochem 36(1):384–394CrossRefPubMedGoogle Scholar
  23. Jouvenceau A, Hédou G, Potier B, Kollen M, Dutar P et al (2006) Partial inhibition of PP1 alters bidirectional synaptic plasticity in the hippocampus. Eur J Neurosci 24(2):564–572CrossRefPubMedGoogle Scholar
  24. Kanematsu T, Yasunaga A, Mizoguchi Y, Kuratani A, Kittler JT, Jovanovic JN, Takenaka K, Nakayama KI, Fukami K, Takenawa T, Moss SJ, Nabekura J, Hirata M (2006) Modulation of GABA(A) receptor phosphorylation and membrane trafficking by phospholipase C-related inactive protein/protein phosphatase 1 and 2A signaling complex underlying brain-derived neurotrophic factor-dependent regulation of GABAergic inhibition. J Biol Chem 281(31):22180–22189CrossRefPubMedGoogle Scholar
  25. Kelker MS, Page R, Peti W (2009) Crystal structures of protein phosphatase-1 bound to nodularin-R and tautomycin: a novel scaffold for structure-based drug design of serine/threonine phosphatase inhibitors. J Mol Biol 385(1):11–21CrossRefPubMedGoogle Scholar
  26. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J et al (2009) The sequence alignment/map format and SAM tools. Bioinformatics 25(16):2078–2079CrossRefPubMedPubMedCentralGoogle Scholar
  27. Liu R, Correll RN, Davis J, Vagnozzi RJ, York AJ et al (2015) Cardiac-specific deletion of protein phosphatase 1β promotes increased myofilament protein phosphorylation and contractile alterations. J Mol Cell Cardiol 87:204–213CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lupski JR, Gonzaga-Jauregui C, Yang Y, Bainbridge MN, Jhangiani S et al (2013) Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy. Genome Med 5(6):57CrossRefPubMedPubMedCentralGoogle Scholar
  29. Maynes JT, Bateman KS, Cherney MM, Das AK, Luu HA et al (2001) Structal structure of the tumor-promoter okadaic acid bound to protein phosphatase-1. J Biol Chem 276(47):44078–44082CrossRefPubMedGoogle Scholar
  30. Moorhead G, Johnson D, Morrice N, Cohen P (1998) The major myosin phosphatase in skeletal muscle is a complex between the β isoform of protein phosphatase 1 and the MYPT2 gene product. FEBS Lett 438:141–144CrossRefPubMedGoogle Scholar
  31. Pereira SR, Vasconcelos VM, Antunes A (2011) The phosphoprotein phosphatase family of Ser/Thr phosphatases as principal targets of naturally occurring toxins. Crit Rev Toxicol 41(2):83–110CrossRefPubMedGoogle Scholar
  32. Peti W, Nairn AC, Page R (2013) Structural basis for protein phosphatase 1 regulation and specificity. FEBS J 280(2):596–611CrossRefPubMedGoogle Scholar
  33. Pribiag H, Stellwagen D (2013) TNF-α downregulates inhibitory neurotransmission through protein phosphatase 1-dependent trafficking of GABA(A) receptors. J Neurosci 33(40):15879–15893CrossRefPubMedGoogle Scholar
  34. Rodriguez-Viciana P, Oses-Prieto J, Burlingame A, Fried M, McCormick F (2006) A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity. Mol Cell 22(2):217–230CrossRefPubMedGoogle Scholar
  35. Saadat M, Kakinoki Y, Mizuno Y, Kikuchi K, Yoshida MC (1994) Chromosomal localization of human, rat, and mouse protein phosphatase type 1 beta catalytic subunit genes (PPP1CB) by fluorescence in situ hybridization. Jpn J Genet 69(6):697–700CrossRefPubMedGoogle Scholar
  36. Shang L, Henderson LB, Cho MT, Petrey DS, Fong CT et al (2016) De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism. Neurogenetics 17(1):43–49CrossRefPubMedGoogle Scholar
  37. Shimizu N, Ishitani S, Sato A, Shibuya H, Ishitani T (2014) Hipk2 and PP1c cooperate to maintain Dvl protein levels required for Wnt signal transduction. Cell Rep. 8(5):1391–1404CrossRefPubMedGoogle Scholar
  38. van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA et al (2011) Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 58(21):2241–2247CrossRefPubMedGoogle Scholar
  39. Vissers LE, Gilissen C, Veltman JA (2016) Genetic studies in intellectual disability and related disorders. Nat Rev Genet 17(1):9–18CrossRefPubMedGoogle Scholar
  40. Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164CrossRefPubMedPubMedCentralGoogle Scholar
  41. Yang Y, Primrose DA, Leung AC, Fitzsimmons RB, McDermand MC, Missellbrook A, Haskins J, Smylie AS, Hughes SC (2012) The PP1 phosphatase flapwing regulates the activity of Merlin and Moesin in Drosophila. Dev Biol 361(2):412–426CrossRefPubMedGoogle Scholar
  42. Zablotsky B, Black LI, Maenner MJ, Schieve LA, Blumberg SJ (2015) Estimated prevalence of autism and other developmental disabilities following questionnaire changes in the 2014 national health interview survey. Natl Health. Stat Report 87:1–20Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Lijiang Ma
    • 1
  • Yavuz Bayram
    • 2
  • Heather M. McLaughlin
    • 3
  • Megan T. Cho
    • 3
  • Alyson Krokosky
    • 4
  • Clesson E. Turner
    • 4
  • Kristin Lindstrom
    • 5
  • Caleb P. Bupp
    • 6
  • Katey Mayberry
    • 6
  • Weiyi Mu
    • 7
  • Joann Bodurtha
    • 7
  • Veronique Weinstein
    • 8
  • Neda Zadeh
    • 9
  • Wendy Alcaraz
    • 10
  • Zöe Powis
    • 10
  • Yunru Shao
    • 2
  • Daryl A. Scott
    • 2
    • 11
  • Andrea M. Lewis
    • 2
  • Janson J. White
    • 2
  • Shalani N. Jhangiani
    • 2
    • 12
  • Elif Yilmaz Gulec
    • 13
  • Seema R. Lalani
    • 2
  • James R. Lupski
    • 2
    • 12
    • 14
    • 15
  • Kyle Retterer
    • 3
  • Rhonda E. Schnur
    • 3
  • Ingrid M. Wentzensen
    • 3
  • Sherri Bale
    • 3
  • Wendy K. Chung
    • 1
    Email author
  1. 1.Department of PediatricsColumbia University Medical CenterNew YorkUSA
  2. 2.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  3. 3.GeneDxGaithersburgUSA
  4. 4.Walter Reed National Military Medical CenterBethesdaUSA
  5. 5.Division of Genetics and MetabolismPhoenix Children’s HospitalPhoenixUSA
  6. 6.Spectrum HealthGrand RapidsUSA
  7. 7.McKusick-Nathans Institute of Genetic MedicineJohns Hopkins UniversityBaltimoreUSA
  8. 8.Division of Genetics and MetabolismChildren’s National Medical CenterWashingtonUSA
  9. 9.Genetics CenterOrangeUSA
  10. 10.Ambry GeneticsAliso ViejoUSA
  11. 11.Department of Molecular Physiology and BiophysicsBaylor College of MedicineHoustonUSA
  12. 12.Human Genome Sequencing CenterBaylor College of MedicineHoustonUSA
  13. 13.Medical Genetics SectionKanuni Sultan Suleyman Training and Research HospitalIstanbulTurkey
  14. 14.Texas Children’s HospitalHoustonUSA
  15. 15.Department of PediatricsBaylor College of MedicineHoustonUSA

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