Abstract
Autism is a neurodevelopmental disorder clinically characterized by impairment of social interaction, deficits in verbal communication, as well as stereotypic and repetitive behaviors. Several studies have implicated that abnormal synaptogenesis was involved in the incidence of autism. Neuroligins are postsynaptic cell adhesion molecules and interacted with neurexins to regulate the fine balance between excitation and inhibition of synapses. Recently, mutation analysis, cellular and mice models hinted neuroligin mutations probably affected synapse maturation and function. In this study, four missense variations [p.G426S (NLGN3), p.G84R (NLGN4X), p.Q162 K (NLGN4X) and p.A283T (NLGN4X)] in four different unrelated patients have been identified by PCR and direct sequencing. These four missense variations were absent in the 453 controls and have not been reported in 1000 Genomes Project. Bioinformatic analysis of the four missense variations revealed that p.G84R and p.A283T were “Probably Damaging”. The variations may cause abnormal synaptic homeostasis and therefore trigger the patients more predisposed to autism. By case–control analysis, we identified the common SNPs (rs3747333 and rs3747334) in the NLGN4X gene significantly associated with risk for autism [p = 5.09E-005; OR 4.685 (95 % CI 2.073–10.592)]. Our data provided a further evidence for the involvement of NLGN3 and NLGN4X gene in the pathogenesis of autism in Chinese population.
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Lainhart JE, Ozonoff S, Coon H, Krasny L, Dinh E, Nice J, McMahon W (2002) Autism, regression, and the broader autism phenotype. Am J Med Genet 113:231–237
Keller F, Persico AM (2003) The neurobiological context of autism. Mol Neurobiol 28:1–22
Volkmar FR, Pauls D (2003) Autism. Lancet 362:1133–1141
Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcin C, Montiel-Nava C, Patel V, Paula CS, Wang C, Yasamy MT, Fombonne E (2012) Global prevalence of autism and other pervasive developmental disorders. Autism Res 5:160–179
Sutcliffe JS (2008) Genetics. Insights into the pathogenesis of autism. Science 321:208–209
Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25:63–77
Szatmari P, Jones MB, Zwaigenbaum L, MacLean JE (1998) Genetics of autism: overview and new directions. J Autism Dev Disord 28:351–368
Rutter M (2000) Genetic studies of autism: from the 1970s into the millennium. J Abnorm Child Psychol 28:3–14
Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E, Coleman M, Zappella M, Aschauer H, Van Maldergem L, Penet C, Feingold J, Brice A, Leboyer M (1999) Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. Hum Mol Genet 8:805–812
Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 34:27–29
Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, David A, Moizard MP, Raynaud M, Ronce N, Lemonnier E, Calvas P, Laudier B, Chelly J, Fryns JP, Ropers HH, Hamel BC, Andres C, Barthelemy C, Moraine C, Briault S (2004) X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet 74:552–557
Lawson-Yuen A, Saldivar JS, Sommer S, Picker J (2008) Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur J Hum Genet 16:614–618
Thomas NS, Sharp AJ, Browne CE, Skuse D, Hardie C, Dennis NR (1999) Xp deletions associated with autism in three females. Hum Genet 104:43–48
Ichtchenko K, Nguyen T, Sudhof TC (1996) Structures, alternative splicing, and neurexin binding of multiple neuroligins. J Biol Chem 271:2676–2682
Levinson JN, El-Husseini A (2007) A crystal-clear interaction: relating neuroligin/neurexin complex structure to function at the synapse. Neuron 56:937–939
Yan J, Feng J, Schroer R, Li W, Skinner C, Schwartz CE, Cook EH, Sommer SS Jr (2008) Analysis of the neuroligin 4Y gene in patients with autism. Psychiatr Genet 18:204–207
Yan J, Oliveira G, Coutinho A, Yang C, Feng J, Katz C, Sram J, Bockholt A, Jones IR, Craddock N, Cook EH Jr, Vicente A, Sommer SS (2005) Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol Psychiatry 10:329–332
Talebizadeh Z, Lam DY, Theodoro MF, Bittel DC, Lushington GH, Butler MG (2006) Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism. J Med Genet 43:e21
Chih B, Afridi SK, Clark L, Scheiffele P (2004) Disorder-associated mutations lead to functional inactivation of neuroligins. Hum Mol Genet 13:1471–1477
Daoud H, Bonnet-Brilhault F, Vedrine S, Demattei MV, Vourc’h P, Bayou N, Andres CR, Barthelemy C, Laumonnier F, Briault S (2009) Autism and nonsyndromic mental retardation associated with a de novo mutation in the NLGN4X gene promoter causing an increased expression level. Biol Psychiatry 66:906–910
Zhang C, Milunsky JM, Newton S, Ko J, Zhao G, Maher TA, Tager-Flusberg H, Bolliger MF, Carter AS, Boucard AA, Powell CM, Sudhof TC (2009) A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. J Neurosci 29:10843–10854
Ey E, Leblond CS, Bourgeron T (2011) Behavioral profiles of mouse models for autism spectrum disorders. Autism Res 4:5–16
Liu Y, Hu Z, Xun G, Peng Y, Lu L, Xu X, Xiong Z, Xia L, Liu D, Li W, Zhao J, Xia K (2012) Mutation analysis of the NRXN1 gene in a Chinese autism cohort. J Psychiatr Res 46:630–634
Li X, Hu Z, He Y, Xiong Z, Long Z, Peng Y, Bu F, Ling J, Xun G, Mo X, Pan Q, Zhao J, Xia K (2010) Association analysis of CNTNAP2 polymorphisms with autism in the Chinese Han population. Psychiatr Genet 20:113–117
Koehnke J, Jin X, Budreck EC, Posy S, Scheiffele P, Honig B, Shapiro L (2008) Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2. Proc Natl Acad Sci USA 105:1873–1878
Sudhof TC (2008) Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455:903–911
Tsigelny I, Shindyalov IN, Bourne PE, Sudhof TC, Taylor P (2000) Common EF-hand motifs in cholinesterases and neuroligins suggest a role for Ca2+ binding in cell surface associations. Protein Sci 9:180–185
Nguyen T, Sudhof TC (1997) Binding properties of neuroligin 1 and neurexin 1 beta reveal function as heterophilic cell adhesion molecules. J Biol Chem 272:26032–26039
Acknowledgments
We thank the patients and their families for agreeing to participate in this study and special teachers whose participation made this project possible. We also thank Cong Wang and Haoying Hao for sequencing, Jiada Li for manuscript revision. We were appreciated for the help and advices of our colleagues. This study was supported by the National Basic Research Program 973 of China (Grant No. 2012CB 517902, 2010 CB 529601) and the National Natural Science Foundation of China (Grant No. 81330027, 81161120544, 31301023).
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Xiaojuan Xu, Zhimin Xiong and Lusi Zhang contributed equally to this study.
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Xu, X., Xiong, Z., Zhang, L. et al. Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients. Mol Biol Rep 41, 4133–4140 (2014). https://doi.org/10.1007/s11033-014-3284-5
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DOI: https://doi.org/10.1007/s11033-014-3284-5