Genomics & Informatics

  • 제19권4호
  • /
  • Pages.44.1-44.9
  • /
  • 2021
  • /
  • 1598-866X(pISSN)
  • /
  • 2234-0742(eISSN)
한국유전체학회 (Korea Genome Organization)
권호 표지
DOI QR코드

DOI QR Code

Genetic analysis of the postsynaptic transmembrane X-linked neuroligin 3 gene in autism

  • Hegde, Rajat (Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B.M Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University)) ;
  • Hegde, Smita (Karnataka Institute for DNA Research (KIDNAR)) ;
  • Kulkarni, Suyamindra S. (Karnataka Institute for DNA Research (KIDNAR)) ;
  • Pandurangi, Aditya (Department of Psychiatry, Dharwad Institute of Mental Health and Neurosciences) ;
  • Gai, Pramod B. (Karnataka Institute for DNA Research (KIDNAR)) ;
  • Das, Kusal K. (Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B.M Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University))
  • 투고 : 2021.04.21
  • 심사 : 2021.12.09
  • 발행 : 2021.12.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Autism is a complex neurodevelopmental disorder, the prevalence of which has increased drastically in India in recent years. Neuroligin is a type I transmembrane protein that plays a crucial role in synaptogenesis. Alterations in synaptic genes are most commonly implicated in autism and other cognitive disorders. The present study investigated the neuroligin 3 gene in the Indian autistic population by sequencing and in silico pathogenicity prediction of molecular changes. In total, 108 clinically described individuals with autism were included from the North Karnataka region of India, along with 150 age-, sex-, and ethnicity-matched healthy controls. Genomic DNA was extracted from peripheral blood, and exonic regions were sequenced. The functional and structural effects of variants of the neuroligin 3 protein were predicted. One coding sequence variant (a missense variant) and four non-coding variants (two 5'-untranslated region [UTR] variants and two 3'-UTR variants) were recorded. The novel missense variant was found in 25% of the autistic population. The C/C genotype of c.551T>C was significantly more common in autistic children than in controls (p = 0.001), and a significantly increased risk of autism (24.7-fold) was associated with this genotype (p = 0.001). The missense variant showed pathogenic effects and high evolutionary conservation over the functions of the neuroligin 3 protein. In the present study, we reported a novel missense variant, V184A, which causes abnormal neuroligin 3 and was found with high frequency in the Indian autistic population. Therefore, neuroligin is a candidate gene for future molecular investigations and functional analysis in the Indian autistic population.

키워드

과제정보

We thank all the autistic individuals and their parents and guardians for agreeing to participate in the study. We also thank all the special schools for participating in our study. We thank the Karnataka Institute for DNA Research (KIDNAR), Dharwad and Shri B.M Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University), Vijayapura for their constant support throughout the research. This study was supported by Grant-in-Aid for research from the Department of Higher Education, Govt. of Karnataka, India (Grant No: Department of Higher Education, ED 15 UKV 2018, Bangalore, date: 12-13-2018).

참고문헌

  1. Spence SJ. The genetics of autism. Semin Pediatr Neurol 2004;11:196-204. https://doi.org/10.1016/j.spen.2004.07.003
  2. Chen JA, Penagarikano O, Belgard TG, Swarup V, Geschwind DH. The emerging picture of autism spectrum disorder: genetics and pathology. Annu Rev Pathol 2015;10:111-144. https://doi.org/10.1146/annurev-pathol-012414-040405
  3. Kanner L. Follow-up study of eleven autistic children originally reported in 1943. J Autism Child Schizophr 1971;1:119-145. https://doi.org/10.1007/BF01537953
  4. Pampanos A, Volaki K, Kanavakis E, Papandreou O, Youroukos S, Thomaidis L, et al. A substitution involving the NLGN4 gene associated with autistic behavior in the Greek population. Genet Test Mol Biomarkers 2009;13:611-615. https://doi.org/10.1089/gtmb.2009.0005
  5. De Rubeis S, Buxbaum JD. Genetics and genomics of autism spectrum disorder: embracing complexity. Hum Mol Genet 2015;24:R24-R31. https://doi.org/10.1093/hmg/ddv273
  6. Ramaswami G, Geschwind DH. Genetics of autism spectrum disorder. Handb Clin Neurol 2018;147:321-329. https://doi.org/10.1016/B978-0-444-63233-3.00021-X
  7. Bourgeron T. Current knowledge on the genetics of autism and propositions for future research. C R Biol 2016;339:300-307. https://doi.org/10.1016/j.crvi.2016.05.004
  8. de la Torre-Ubieta L, Won H, Stein JL, Geschwind DH. Advancing the understanding of autism disease mechanisms through genetics. Nat Med 2016;22:345-361. https://doi.org/10.1038/nm.4071
  9. Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC, et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 2003;34:27-29. https://doi.org/10.1038/ng1136
  10. Raina SK, Chander V, Bhardwaj AK, Kumar D, Sharma S, Kashyap V, et al. Prevalence of autism spectrum disorder among rural, urban, and tribal children (1-10 years of age). J Neurosci Rural Pract 2017;8:368-374. https://doi.org/10.4103/jnrp.jnrp_329_16
  11. Chauhan A, Singh M, Jaiswal N, Agarwal A, Sahu JK, Singh M. Prevalence of cerebral palsy in Indian children: a systematic review and meta-analysis. Indian J Pediatr 2019;86:1124-1130. https://doi.org/10.1007/s12098-019-03024-0
  12. Chen X, Liu H, Shim AH, Focia PJ, He X. Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions. Nat Struct Mol Biol 2008;15:50-56. https://doi.org/10.1038/nsmb1350
  13. Nguyen TA, Lehr AW, Roche KW. Neuroligins and neurodevelopmental disorders: X-linked genetics. Front Synaptic Neurosci 2020;12:33. https://doi.org/10.3389/fnsyn.2020.00033
  14. Nguyen TA, Wu K, Pandey S, Lehr AW, Li Y, Bemben MA, et al. A cluster of autism-associated variants on X-linked NLGN4X functionally resemble NLGN4Y. Neuron 2020;106:759-768. https://doi.org/10.1016/j.neuron.2020.03.008
  15. Lawson-Yuen A, Saldivar JS, Sommer S, Picker J. Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur J Hum Genet 2008;16:614-618. https://doi.org/10.1038/sj.ejhg.5202006
  16. Yan J, Oliveira G, Coutinho A, Yang C, Feng J, Katz C, et al. Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol Psychiatry 2005;10:329-332. https://doi.org/10.1038/sj.mp.4001629
  17. Kent R, Simonoff E. Prevalence of anxiety in autism spectrum disorders. In: Anxiety in Children and Adolescents with Autism Spectrum Disorder: Evidence-Based Assessment and Treatment (Kerns CM, Renno P, Storch EA, Kendall PC, Wood JJ, eds.). San Diego: Elsevier Inc., 2017. pp. 5-32.
  18. Volaki K, Pampanos A, Kitsiou-Tzeli S, Vrettou C, Oikonomakis V, Sofocleous C, et al. Mutation screening in the Greek population and evaluation of NLGN3 and NLGN4X genes causal factors for autism. Psychiatr Genet 2013;23:198-203. https://doi.org/10.1097/YPG.0b013e3283643644
  19. Ylisaukko-oja T, Rehnstrom K, Auranen M, Vanhala R, Alen R, Kempas E, et al. Analysis of four neuroligin genes as candidates for autism. Eur J Hum Genet 2005;13:1285-1292. https://doi.org/10.1038/sj.ejhg.5201474
  20. Quartier A, Courraud J, Thi Ha T, McGillivray G, Isidor B, Rose K, et al. Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment. Hum Mutat 2019;40:2021-2032. https://doi.org/10.1002/humu.23836
  21. Yu J, He X, Yao D, Li Z, Li H, Zhao Z. A sex-specific association of common variants of neuroligin genes (NLGN3 and NLGN4X) with autism spectrum disorders in a Chinese Han cohort. Behav Brain Funct 2011;7:13. https://doi.org/10.1186/1744-9081-7-13
  22. Redin C, Gerard B, Lauer J, Herenger Y, Muller J, Quartier A, et al. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. J Med Genet 2014;51:724-736. https://doi.org/10.1136/jmedgenet-2014-102554
  23. Steinberg KM, Ramachandran D, Patel VC, Shetty AC, Cutler DJ, Zwick ME. Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder. Mol Autism 2012;3:8. https://doi.org/10.1186/2040-2392-3-8
  24. Yanagi K, Kaname T, Wakui K, Hashimoto O, Fukushima Y, Naritomi K. Identification of four novel synonymous substitutions in the X-linked genes neuroligin 3 and neuroligin 4X in Japanese patients with autistic spectrum disorder. Autism Res Treat 2012;2012:724072. https://doi.org/10.1155/2012/724072
  25. Blasi F, Bacchelli E, Pesaresi G, Carone S, Bailey AJ, Maestrini E, et al. Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection. Am J Med Genet B Neuropsychiatr Genet 2006;141B:220-221. https://doi.org/10.1002/ajmg.b.30287
  26. Talebizadeh Z, Lam DY, Theodoro MF, Bittel DC, Lushington GH, Butler MG. Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism. J Med Genet 2006;43:e21. https://doi.org/10.1136/jmg.2005.036897
  27. Landini M, Merelli I, Raggi ME, Galluccio N, Ciceri F, Bonfanti A, et al. Association analysis of noncoding variants in neuroligins 3 and 4X genes with autism spectrum disorder in an Italian cohort. Int J Mol Sci 2016;17:1765. https://doi.org/10.3390/ijms17101765