Skip to main content
Log in

Ras-like without CAAX 2 (RIT2): a susceptibility gene for autism spectrum disorder

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Ras-like without CAAX2 (RIT2) which encodes a GTP-binding protein has recently been reported as a new susceptibility gene for Autism Spectrum Disorders (ASD) in a genome-wide association study. Since the gene is suggested to be involved in the pathogenesis of different neurological diseases, we investigated the association of two single nucleotide polymorphisms (SNP) rs16976358 and rs4130047 of this gene with ASD in Iranian patients. A total of 1004 individuals, comprising 532 ASD cases and 472 healthy subjects participated in this study. Allele frequency analyses showed significant over-presentation of rs16976358-C allele in cases versus controls (P < 0.0001). In addition, rs16976358 CC genotype (OR (95% CI) =3.57(1.72–7.69) and P < 0.0001) and rs4130047 CC genotype (OR (95% CI) =0.64(0.43–0.97) and P = 0.035) were associated with ASD in recessive inheritance model. Besides, haplotype analysis demonstrated an association between the C/T haplotype block (rs16976358/rs4130047) and ASD (OR (95%CI) = 0.44 (0.31–0.62), P < 0.0001). Altogether, our findings provided additional confirmation for the RIT2 gene participation in ASD risk and suggested the rs16976358 variant as a possible genetic risk factor for this disorder.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bossers K, Meerhoff G, Balesar R, Van Dongen JW, Kruse CG, Swaab DF, Verhaagen J (2009) Analysis of gene expression in Parkinson's disease: possible involvement of neurotrophic support and axon guidance in dopaminergic cell death. Brain Pathol 19:91–107

    Article  CAS  PubMed  Google Scholar 

  • Burbach JPH, VAN Der Zwaag B (2009) Contact in the genetics of autism and schizophrenia. Trends Neurosci 32:69–72

    Article  CAS  PubMed  Google Scholar 

  • Collins A, Ke X (2012) Primer1: primer design web service for tetra-primer ARMS-PCR. The Open Bioinformatics Journal 6:55–58

    Article  Google Scholar 

  • Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM, Francke U, Mountain JL, Goldman SM, Tanner CM, Langston JW (2011) Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease. PLoS Genet 7:e1002141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emamalizadeh B, Jamshidi J, Movafagh A, Ohadi M, Kazeminasab S, Biglarian A, Taghavi S, Motallebi M, Fazeli A, Ahmadifard A (2016) RIT2 polymorphisms: is there a differential association? Mol Neurobiol:1–7

  • Geschwind DH (2008) Autism: many genes, common pathways? Cell 135:391–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glessner JT, Connolly JJ, Hakonarson H (2014) Genome-wide association studies of autism. Current Behavioral Neuroscience Reports 1:234–241

    Article  Google Scholar 

  • Hamshere ML, Walters JTR, Smith R, Richards AL, Green E, Grozeva D, JONES I, Forty L, Jones L, Gordon-Smith K (2013) Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the schizophrenia PGC. Mol Psychiatry 18:708–712

    Article  CAS  PubMed  Google Scholar 

  • Iossifov I, Zheng T, Baron M, Gilliam TC, Rzhetsky A (2008) Genetic-linkage mapping of complex hereditary disorders to a whole-genome molecular-interaction network. Genome Res 18:1150–1162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kirov G, Gumus D, Chen W, Norton N, Georgieva L, Sari M, O’donovan MC, Erdogan F, Owen MJ, Ropers H-H (2008) Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet 17:458–465

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kwan KY (2013) Transcriptional dysregulation of neocortical circuit assembly in ASD. Int Rev Neurobiol 113:167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Zhao L, You Y, Lu T, Jia M, Yu H, Ruan Y, Yue W, Liu J, Lu L (2015) Schizophrenia related variants in CACNA1C also confer risk of autism. PLoS One 10:e0133247

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin C-H, Chen M-L, Yu C-Y, Wu R-M (2013) RIT2 variant is not associated with Parkinson's disease in a Taiwanese population. Neurobiology of Aging 34:2236. e1–2236. e3

    Article  CAS  Google Scholar 

  • Liu X, Shimada T, Otowa T, Wu YY, Kawamura Y, Tochigi M, Iwata Y, Umekage T, Toyota T, Maekawa M. (2015a). Genome-wide association study of autism Spectrum disorder in the east Asian populations. Autism Research 9(3):340-349

  • Liu Z-H, Guo J-F, Wang Y-Q, Li K, Sun Q-Y, Yan X-X, Xu C-S, Tang B-S (2015b) Assessment of RIT2 rs12456492 association with Parkinson's disease in Mainland China. Neurobiology of Aging 36:1600. e9–1600. e11

    Article  CAS  Google Scholar 

  • Lu Y, Liu W, Tan K, Peng J, Zhu Y, Wang X (2015) Genetic association of RIT2 rs12456492 polymorphism and Parkinson’s disease susceptibility in Asian populations: a meta-analysis. Scientific reports 5. doi:10.1038/srep13805

  • Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82:477–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitin N, Rossman KL, DER CJ (2005) Signaling interplay in Ras superfamily function. Curr Biol 15:R563–R574

    Article  CAS  PubMed  Google Scholar 

  • Navaroli DM, Stevens ZH, Uzelac Z, Gabriel L, King MJ, Lifshitz LM, Sitte HH, Melikian HE (2011) The plasma membrane-associated GTPase Rin interacts with the dopamine transporter and is required for protein kinase C-regulated dopamine transporter trafficking. J Neurosci 31:13758–13770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nie K, Feng S-J, Tang H-M, Ma G-X, Gan R, Zhao X, Zhao J-H, Wang L-M, Huang Z-H, Huang J (2015) RIT2 polymorphism is associated with Parkinson's disease in a Han Chinese population. Neurobiology of Aging 36:1603. e15–1603. e17

    Article  CAS  Google Scholar 

  • Noroozi R, Taheri M, Movafagh A, Mirfakhraie R, Solgi G, Sayad A, Mazdeh M, Darvish H (2016) Glutamate receptor, metabotropic 7 (GRM7) gene variations and susceptibility to autism: a case–control study. Autism Res 9:1161–1168

  • Pankratz N, Beecham GW, Destefano AL, Dawson TM, Doheny KF, Factor SA, Hamza TH, Hung AY, Hyman BT, Ivinson AJ (2012) Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2. Ann Neurol 71:370–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ronemus M, Iossifov I, Levy D, Wigler M (2014) The role of de novo mutations in the genetics of autism spectrum disorders. Nat Rev Genet 15:133–141

    Article  CAS  PubMed  Google Scholar 

  • Rosenfeld JA, Ballif BC, Torchia BS, Sahoo T, Ravnan JB, Schultz R, Lamb A, Bejjani BA, Shaffer LG (2010) Copy number variations associated with autism spectrum disorders contribute to a spectrum of neurodevelopmental disorders. Genetics in Medicine 12:694–702

    Article  PubMed  Google Scholar 

  • Safari MR, Omrani MD, Noroozi R, Sayad A, Sarrafzadeh S, Komaki A, Manjili FA, Mazdeh M, Ghaleiha A, Taheri M (2016) Synaptosome-associated protein 25 (SNAP25) gene association analysis revealed risk variants for ASD, in Iranian population. J Mol Neurosci 1–7. doi:10.1007/s12031-016-0860-2

  • Safari MR, GHAFOURI-Fard S, Noroozi R, Sayad A, Omrani MD, Komaki A, Eftekharian MM, Taheri M (2017) FOXP3 gene variations and susceptibility to autism: a case–control study. Gene 596:119–122

    Article  CAS  PubMed  Google Scholar 

  • Shaw C, Sheth S, Li D, Tomljenovic L (2014) Etiology of autism spectrum disorders: genes, environment, or both. OA Autism 2(2):11

  • Sole X, Guinó E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22:1928–1929

    Article  CAS  PubMed  Google Scholar 

  • Tager-Flusberg H, Paul R, Lord C (2005) Language and communication in autism. Handbook of autism and pervasive developmental disorders 1:335–364

    Google Scholar 

  • Takai Y, Sasaki T, Matozaki T (2001) Small GTP-binding proteins. Physiol Rev 81:153–208

    CAS  PubMed  Google Scholar 

  • Vigil D, Cherfils J, Rossman KL, Der CJ (2010) Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 10:842–857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J-Y, Gong M-Y, Ye Y-L, Ye J-M, Lin G-L, Zhuang Q-Q, Zhang X, Zhu J-H (2015) The RIT2 and STX1B polymorphisms are associated with Parkinson's disease. Parkinsonism Relat Disord 21:300–302

    Article  PubMed  Google Scholar 

  • Ward LD, KELLIS M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40:D930–D934

    Article  CAS  PubMed  Google Scholar 

  • Yang W, Liu J, Zheng F, JIA M, Zhao L, Lu T, Ruan Y, Zhang J, Yue W, Zhang D (2013) The evidence for association of ATP2B2 polymorphisms with autism in Chinese Han population. PLoS One 8:e61021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Wahlin K, Li Y, Masuda T, Yang Z, Zack DJ, Esumi N (2013) RIT2, a neuron-specific small guanosine triphosphatase, is expressed in retinal neuronal cells and its promoter is modulated by the POU4 transcription factors. Mol Vis 19:1371–1386

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Niu M, Li H, Xie A (2015) RIT2 rs12456492 polymorphism and the risk of Parkinson’s disease: a meta-analysis. Neurosci Lett 602:167–171

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all of the patients participated in this study and are grateful to the Department of Medical Genetics of Shahid Beheshti University of Medical Science for their support of this work. We also thank the staff of the Department of Medical Genetics for technical support during the study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mohammad Taheri.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hamedani, S.Y., Gharesouran, J., Noroozi, R. et al. Ras-like without CAAX 2 (RIT2): a susceptibility gene for autism spectrum disorder. Metab Brain Dis 32, 751–755 (2017). https://doi.org/10.1007/s11011-017-9969-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-017-9969-4

Keywords

Navigation