Overrepresentation of genetic variation in the AnkyrinG interactome is related to a range of neurodevelopmental disorders


Upon the discovery of numerous genes involved in the pathogenesis of neurodevelopmental disorders, several studies showed that a significant proportion of these genes converge on common pathways and protein networks. Here, we used a reversed approach, by screening the AnkyrinG protein-protein interaction network for genetic variation in a large cohort of 1009 cases with neurodevelopmental disorders. We identified a significant enrichment of de novo potentially disease-causing variants in this network, confirming that this protein network plays an important role in the emergence of several neurodevelopmental disorders.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Schematic overview of the ANK3 protein-protein interaction network members.


  1. 1.

    APA: American Psychiatric Association. Diagnostic and statistical manual of mental disorders DSM-V, Fifth ed., Text revision. Washington DC: American Psychiatric Association; 2013.

  2. 2.

    Oeseburg B, Dijkstra GJ, Groothoff JW, Reijneveld SA, Jansen DE. Prevalence of chronic health conditions in children with intellectual disability: a systematic literature review. Intellect Dev Dis. 2011;49:59–85.

    Google Scholar 

  3. 3.

    Ben-Shachar S, Lanpher B, German JR, Qasaymeh M, Potocki L, Nagamani SC, et al. Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J Med Genet. 2009;46:382–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455:232–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008;358:667–75.

    CAS  PubMed  Google Scholar 

  6. 6.

    McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009;41:1223–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Zufferey F, Sherr EH, Beckmann ND, Hanson E, Maillard AM, Hippolyte L, et al. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. J Med Genet. 2012;49:660–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    O’Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science (New York, NY). 2012;338:1619–22.

    Google Scholar 

  9. 9.

    Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, et al. De novo gene disruptions in children on the autistic spectrum. Neuron. 2012;74:285–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367:1921–9.

    PubMed  Google Scholar 

  11. 11.

    Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380:1674–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Krumm N, O’Roak BJ, Shendure J, Eichler EE. A de novo convergence of autism genetics and molecular neuroscience. Trends Neurosci. 2014;37:95–105.

    CAS  PubMed  Google Scholar 

  13. 13.

    Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014;94:677–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    van Bokhoven H. Genetic and epigenetic networks in intellectual disabilities. Annu Rev Genet. 2011;45:81–104.

    PubMed  Google Scholar 

  15. 15.

    Davis JQ, Lambert S, Bennett V. Molecular composition of the node of Ranvier: identification of ankyrin-binding cell adhesion molecules neurofascin (mucin+/third FNIII domain-) and NrCAM at nodal axon segments. J Cell Biol. 1996;135:1355–67.

    CAS  PubMed  Google Scholar 

  16. 16.

    Zhou D, Lambert S, Malen PL, Carpenter S, Boland LM, Bennett V. AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing. J Cell Biol. 1998;143:1295–304.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Berghs S, Aggujaro D, Dirkx R Jr, Maksimova E, Stabach P, Hermel JM, et al. betaIV spectrin, a new spectrin localized at axon initial segments and nodes of ranvier in the central and peripheral nervous system. J Cell Biol. 2000;151:985–1002.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Pan Z, Kao T, Horvath Z, Lemos J, Sul JY, Cranstoun SD, et al. A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J Neurosci. 2006;26:2599–613.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Jenkins PM, Kim N, Jones SL, Tseng WC, Svitkina TM, Yin HH, et al. Giant ankyrin-G: a critical innovation in vertebrate evolution of fast and integrated neuronal signaling. Proc Natl Acad Sci USA. 2015;112:957–64.

    CAS  PubMed  Google Scholar 

  20. 20.

    Kordeli E, Lambert S, Bennett V. AnkyrinG. A new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier. J Biol Chem. 1995;270:2352–9.

    CAS  PubMed  Google Scholar 

  21. 21.

    Sobotzik JM, Sie JM, Politi C, Del Turco D, Bennett V, Deller T, et al. AnkyrinG is required to maintain axo-dendritic polarity in vivo. Proc Natl Acad Sci USA. 2009;106:17564–9.

    CAS  PubMed  Google Scholar 

  22. 22.

    Smith KR, Kopeikina KJ, Fawcett-Patel JM, Leaderbrand K, Gao R, Schurmann B, et al. Psychiatric risk factor ANK3/ankyrin-G nanodomains regulate the structure and function of glutamatergic synapses. Neuron. 2014;84:399–415.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Ferreira MA, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. 2008;40:1056–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Yuan A, Yi Z, Wang Q, Sun J, Li Z, Du Y, et al. ANK3 as a risk gene for schizophrenia: New data in han Chinese and meta analysis. Am J Med Genet B Neuropsychiatr Genet. 2012;159B:997–1005.

    PubMed  Google Scholar 

  25. 25.

    Schulze TG, Detera-Wadleigh SD, Akula N, Gupta A, Kassem L, Steele J, et al. Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder. Mol Psychiatry. 2009;14:487–91.

    CAS  PubMed  Google Scholar 

  26. 26.

    Athanasiu L, Mattingsdal M, Kahler AK, Brown A, Gustafsson O, Agartz I, et al. Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort. J Psychiatr Res. 2010;44:748–53.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Logue MW, Solovieff N, Leussis MP, Wolf EJ, Melista E, Baldwin C, et al. The ankyrin-3 gene is associated with posttraumatic stress disorder and externalizing comorbidity. Psychoneuroendocrinology. 2013;38:2249–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Bi C, Wu J, Jiang T, Liu Q, Cai W, Yu P, et al. Mutations of ANK3 identified by exome sequencing are associated with autism ausceptibility. Hum Mutat. 2012;33:1635–8.

    CAS  PubMed  Google Scholar 

  29. 29.

    Iqbal Z, Vandeweyer G, van der Voet M, Waryah AM, Zahoor MY, Besseling JA, et al. Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders. Hum Mol Genet. 2013;22:1960–70.

    CAS  PubMed  Google Scholar 

  30. 30.

    Brechet A, Fache MP, Brachet A, Ferracci G, Baude A, Irondelle M, et al. Protein kinase CK2 contributes to the organization of sodium channels in axonal membranes by regulating their interactions with ankyrin G. J Cell Biol. 2008;183:1101–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A, McGrath LM, et al. A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014;46:944–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Okur V, Cho MT, Henderson L, Retterer K, Schneider M, Sattler S, et al. De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features. Hum Genet. 2016;135:699–705.

    CAS  PubMed  Google Scholar 

  35. 35.

    Deciphering Developmental Disorders S. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542:433–8.

    Google Scholar 

  36. 36.

    Sarno S, Vaglio P, Meggio F, Issinger OG, Pinna LA. Protein kinase CK2 mutants defective in substrate recognition. Purification and kinetic analysis. J Biol Chem. 1996;271:10595–601.

    CAS  PubMed  Google Scholar 

  37. 37.

    Chiu ATG, Pei SLC, Mak CCY, Leung GKC, Yu MHC, Lee SL, et al. Okur-Chung neurodevelopmental syndrome: Eight additional cases with implications on phenotype and genotype expansion. Clin Genet. 2018;93:880–90.

    CAS  PubMed  Google Scholar 

  38. 38.

    Akahira-Azuma M, Tsurusaki Y, Enomoto Y, Mitsui J, Kurosawa K. Refining the clinical phenotype of Okur-Chung neurodevelopmental syndrome. Hum Genome Var. 2018;5:18011.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Wallace RH, Wang DW, Singh R, Scheffer IE, George AL Jr, Phillips HA, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet. 1998;19:366–70.

    CAS  Google Scholar 

  40. 40.

    Lelieveld SH, Reijnders MR, Pfundt R, Yntema HG, Kamsteeg EJ, de Vries P, et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci. 2016;19:1194–6.

    CAS  PubMed  Google Scholar 

  41. 41.

    Patino GA, Isom LL. Electrophysiology and beyond: multiple roles of Na+ channel beta subunits in development and disease. Neurosci Lett. 2010;486:53–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Scheffer IE, Harkin LA, Grinton BE, Dibbens LM, Turner SJ, Zielinski MA, et al. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain: J Neurol. 2007;130:100–9.

    Google Scholar 

  43. 43.

    McCormick KA, Isom LL, Ragsdale D, Smith D, Scheuer T, Catterall WA. Molecular determinants of Na+ channel function in the extracellular domain of the beta1 subunit. J Biol Chem. 1998;273:3954–62.

    CAS  PubMed  Google Scholar 

  44. 44.

    Malhotra JD, Koopmann MC, Kazen-Gillespie KA, Fettman N, Hortsch M, Isom LL. Structural requirements for interaction of sodium channel beta 1 subunits with ankyrin. J Biol Chem. 2002;277:26681–8.

    CAS  PubMed  Google Scholar 

  45. 45.

    Fry AE, Rees E, Thompson R, Mantripragada K, Blake P, Jones G, et al. Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy. BMC Med Genet. 2016;17:34.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Weckhuysen S, Mandelstam S, Suls A, Audenaert D, Deconinck T, Claes LRF, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol. 2012;71:15–25.

    CAS  Google Scholar 

  47. 47.

    Papadimitriou S, Gazzo A, Versbraegen N, Nachtegael C, Aerts J, Moreau Y, et al. Predicting disease-causing variant combinations. Proc Natl Acad Sci USA. 2019;116:11878–87.

    CAS  PubMed  Google Scholar 

  48. 48.

    Vissers LELM, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, et al. A de novo paradigm for mental retardation. Nat Genet. 2010;42:1109–12.

    CAS  PubMed  Google Scholar 

  49. 49.

    Beyens M, Boeckx N, Van Camp G, Op de Beeck K, Vandeweyer G. pyAmpli: an amplicon-based variant filter pipeline for targeted resequencing data. BMC Bioinform. 2017;18:554.

    Google Scholar 

  50. 50.

    Vissers LE, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet. 2016;17:9–18.

    CAS  PubMed  Google Scholar 

  51. 51.

    Vandeweyer G, Helsmoortel C, Van Dijck A, Vulto-van Silfhout AT, Coe BP, Bernier R. et al. The Transcriptional Regulator ADNP Links the BAF (SWI/SNF) Complexes With Autism. Am J Med Genet C. 2014;166:315–26.

    CAS  Google Scholar 

  52. 52.

    Kosho T, Okamoto N, Ohashi H, Tsurusaki Y, Imai Y, Hibi-Ko Y, et al. Clinical correlations of mutations affecting six components of the SWI/SNF complex: detailed description of 21 patients and a review of the literature. Am J Med Genet. 2013;161A:1221–37.

    PubMed  Google Scholar 

  53. 53.

    Braat S, Kooy RF. Fragile X syndrome neurobiology translates into rational therapy. Drug Discov Today. 2014;19:510–9.

    PubMed  Google Scholar 

  54. 54.

    Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB Jr, Moine H, Kooy RF, et al. Fragile X syndrome. Nat Rev Dis Prim. 2017;3:17065.

    PubMed  Google Scholar 

  55. 55.

    Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell. 2011;146:247–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Ercument Cicek A, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515:209–15.

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Boyle EA, O’Roak BJ, Martin BK, Kumar A, Shendure J. MIPgen: optimized modeling and design of molecular inversion probes for targeted resequencing. Bioinformatics. 2014;30:2670–2.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43:491–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Untergasser A, Nijveen H, Rao X, Bisseling T, Geurts R, Leunissen JA. Primer3Plus, an enhanced web interface to Primer3. Nucleic Acids Res. 2007;35:W71–4.

    PubMed  PubMed Central  Google Scholar 

Download references


This work was sponsored by a grant from the Fonds Wetenschappelijk Onderzoek - Vlaanderen (FWO) to RFK and GVDW and by a grant from the Netherlands Organization for Health Research and Development (912-12-109) to LELMV and BBAdV.

Author information



Corresponding author

Correspondence to Geert Vandeweyer.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

van der Werf, I.M., Jansen, S., de Vries, P.F. et al. Overrepresentation of genetic variation in the AnkyrinG interactome is related to a range of neurodevelopmental disorders. Eur J Hum Genet (2020). https://doi.org/10.1038/s41431-020-0682-0

Download citation