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ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation

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Abstract

ARHGEF9 resides on Xq11.1 and encodes collybistin, which is crucial in gephyrin clustering and GABAA receptor localization. ARHGEF9 mutations have been identified in patients with heterogeneous phenotypes, including epilepsy of variable severity and intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using next-generation sequencing, we identified a novel mutation, c.868C > T/p.R290C, which co-segregated with epileptic encephalopathy, and validated its association with epileptic encephalopathy. Further analysis revealed that all ARHGEF9 mutations were associated with intellectual disability, suggesting its critical role in psychomotor development. Three missense mutations in the PH domain were not associated with epilepsy, suggesting that the co-occurrence of epilepsy depends on the affected functional domains. Missense mutations with severe molecular alteration in the DH domain, or located in the DH-gephyrin binding region, or adjacent to the SH3-NL2 binding site were associated with severe epilepsy, implying that the clinical severity was potentially determined by alteration of molecular structure and location of mutations. Male patients with ARHGEF9 mutations presented more severe phenotypes than female patients, which suggests a gene-dose effect and supports the pathogenic role of ARHGEF9 mutations. This study highlights the role of molecular alteration in phenotype expression and facilitates evaluation of the pathogenicity of ARHGEF9 mutations in clinical practice.

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References

  1. Kins S, Betz H, Kirsch J (2000) Collybistin, a newly identified brain-specific GEF, induces submembrane clustering of gephyrin. Nat Neurosci 3:22–29

    Article  CAS  PubMed  Google Scholar 

  2. Jedlicka P, Papadopoulos T, Deller T, Betz H, Schwarzacher SW (2009) Increased network excitability and impaired induction of long-term potentiation in the dentate gyrus of collybistin-deficient mice in vivo. Mol Cell Neurosci 41:94–100

    Article  CAS  PubMed  Google Scholar 

  3. Papadopoulos T, Korte M, Eulenburg V, Kubota H, Retiounskaia M, Harvey RJ, Harvey K, O'Sullivan GA, Laube B, Hulsmann S et al (2007) Impaired GABAergic transmission and altered hippocampal synaptic plasticity in collybistin-deficient mice. EMBO J 26:3888–3899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Papadopoulos T, Soykan T (2011) The role of collybistin in gephyrin clustering at inhibitory synapses: facts and open questions. Front Cell Neurosci 5:11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Harvey K, Duguid IC, Alldred MJ, Beatty SE, Ward H, Keep NH, Lingenfelter SE, Pearce BR, Lundgren J, Owen MJ et al (2004) The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering. J Neurosci 24:5816–5826

    Article  CAS  PubMed  Google Scholar 

  6. Lesca G, Till M, Labalme A, Vallee D, Hugonenq C, Philip N, Edery P, Sanlaville D (2011) De novo Xq11.11 microdeletion including ARHGEF9 in a boy with mental retardation, epilepsy, macrosomia, and dysmorphic features. Am J Med Genet A 155A:1706–1711

    Article  PubMed  Google Scholar 

  7. Marco EJ, Abidi FE, Bristow J, Dean WB, Cotter P, Jeremy RJ, Schwartz CE, Sherr EH (2008) ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal. J Med Genet 45:100–105

    Article  CAS  PubMed  Google Scholar 

  8. Machado CO, Griesi-Oliveira K, Rosenberg C, Kok F, Martins S, Passos-Bueno MR, Sertie AL (2016) Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism. Eur J Hum Genet 24:59–65

    Article  PubMed  Google Scholar 

  9. Shimojima K, Sugawara M, Shichiji M, Mukaida S, Takayama R, Imai K, Yamamoto T (2011) Loss-of-function mutation of collybistin is responsible for X-linked mental retardation associated with epilepsy. J Hum Genet 56:561–565

    Article  CAS  PubMed  Google Scholar 

  10. de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C et al (2012) Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 367:1921–1929

    Article  PubMed  Google Scholar 

  11. Long P, May MM, James VM, Granno S, Johnson JP, Tarpey P, Stevenson RE, Harvey K, Schwartz CE, Harvey RJ (2016) Missense mutation R338W in ARHGEF9 in a family with X-linked intellectual disability with variable macrocephaly and macro-orchidism. Front Mol Neurosci 8:83

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bhat G, LaGrave D, Millson A, Herriges J, Lamb AN, Matalon R (2016) Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum disorder. Eur J Med Genet 59:470–473

    Article  PubMed  Google Scholar 

  13. Alber M, Kalscheuer VM, Marco E, Sherr E, Lesca G, Till M, Gradek G, Wiesener A, Korenke C, Mercier S et al (2017) ARHGEF9 disease: phenotype clarification and genotype-phenotype correlation. Neurol Genet e148:3

    Google Scholar 

  14. Klein KM, Pendziwiat M, Eilam A, Gilad R, Blatt I, Rosenow F, Kanaan M, Helbig I, Afawi Z, Israeli-Palestinian Epilepsy Family C (2017) The phenotypic spectrum of ARHGEF9 includes intellectual disability, focal epilepsy and febrile seizures. J Neurol 264:1421–1425

    Article  CAS  PubMed  Google Scholar 

  15. Commission (1981) Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the commission on classification and terminology of the international league against epilepsy. Epilepsia 22:489–501

    Article  Google Scholar 

  16. Commission (1989) Proposal for revised classification of epilepsies and epileptic syndromes. Commission on classification and terminology of the international league against epilepsy. Epilepsia 30:389–399

    Article  Google Scholar 

  17. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW et al (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology, 2005-2009. Epilepsia 51:676–685

    Article  PubMed  Google Scholar 

  18. Roy A, Kucukural A, Zhang Y (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5:725–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang J, Lin ZJ, Liu L, Xu HQ, Shi YW, Yi YH, He N, Liao WP (2017) Epilepsy-associated genes. Seizure 44:11–20

    Article  PubMed  Google Scholar 

  20. Joiner ML, Lee A (2015) Voltage-gated Cav1 channels in disorders of vision and hearing. Curr Mol Pharmacol 8:143–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Del Valle, I., Buonocore, F., Duncan, A.J., Lin, L., Barenco, M., Parnaik, R., Shah, S., Hubank, M., Gerrelli, D., and Achermann, J.C. 2017. A genomic atlas of human adrenal and gonad development. Wellcome Open Res 2:25

  22. Wang G, Yang E, Smith KJ, Zeng Y, Ji G, Connon R, Fangue NA, Cai JJ (2014) Gene expression responses of threespine stickleback to salinity: implications for salt-sensitive hypertension. Front Genet 5:312

    PubMed  PubMed Central  Google Scholar 

  23. Lemke JR, Riesch E, Scheurenbrand T, Schubach M, Wilhelm C, Steiner I, Hansen J, Courage C, Gallati S, Burki S et al (2012) Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia 53:1387–1398

    Article  CAS  PubMed  Google Scholar 

  24. Papadopoulos T, Schemm R, Grubmuller H, Brose N (2015) Lipid binding defects and perturbed synaptogenic activity of a Collybistin R290H mutant that causes epilepsy and intellectual disability. J Biol Chem 290:8256–8270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Saiepour L, Fuchs C, Patrizi A, Sassoe-Pognetto M, Harvey RJ, Harvey K (2010) Complex role of collybistin and gephyrin in GABAA receptor clustering. J Biol Chem 285:29623–29631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Soykan T, Schneeberger D, Tria G, Buechner C, Bader N, Svergun D, Tessmer I, Poulopoulos A, Papadopoulos T, Varoqueaux F et al (2014) A conformational switch in collybistin determines the differentiation of inhibitory postsynapses. EMBO J 33:2113–2133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lindeboom RG, Supek F, Lehner B (2016) The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat Genet 48:1112–1118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Romao L, Inacio A, Santos S, Avila M, Faustino P, Pacheco P, Lavinha J (2000) Nonsense mutations in the human beta-globin gene lead to unexpected levels of cytoplasmic mRNA accumulation. Blood 96:2895–2901

    CAS  PubMed  Google Scholar 

  29. Reddy-Alla S, Schmitt B, Birkenfeld J, Eulenburg V, Dutertre S, Bohringer C, Gotz M, Betz H, Papadopoulos T (2010) PH-domain-driven targeting of collybistin but not Cdc42 activation is required for synaptic gephyrin clustering. Eur J Neurosci 31:1173–1184

    Article  PubMed  Google Scholar 

  30. Kalscheuer VM, Musante L, Fang C, Hoffmann K, Fuchs C, Carta E, Deas E, Venkateswarlu K, Menzel C, Ullmann R et al (2009) A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation. Hum Mutat 30:61–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the family and physicians for participation in our study. We are grateful to the He Shanheng Charity Foundation for contributing to the development of this institute.

Funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81571273, 81501124, and 81571274), Omics-based Precision Medicine of Epilepsy being entrusted by Key Research Project of the Ministry of Science and Technology of China (Grant No. 2016YFC0904400), and Science and Technology Project of Guangzhou (Grant Nos. 201,508,020,011, 201,604,020,161, and 201,607,010,002).

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Correspondence to Na He or Wei-Ping Liao.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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The authors declare that they have no conflict of interest.

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Wang, JY., Zhou, P., Wang, J. et al. ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation. Neurogenetics 19, 9–16 (2018). https://doi.org/10.1007/s10048-017-0528-2

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  • DOI: https://doi.org/10.1007/s10048-017-0528-2

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