{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:28:49Z","timestamp":1790958529879,"version":"4.1.0"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T00:00:00Z","timestamp":1712102400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T00:00:00Z","timestamp":1712102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["MH103398"],"award-info":[{"award-number":["MH103398"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS112480"],"award-info":[{"award-number":["NS112480"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Molecular Autism"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Glutamatergic synapse dysfunction is believed to underlie the development of Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) in many individuals. However, identification of genetic markers that contribute to synaptic dysfunction in these individuals is notoriously difficult. Based on genomic analysis, structural modeling, and functional data, we recently established the involvement of the TRIO-RAC1 pathway in ASD and ID. Furthermore, we identified a pathological <jats:italic>de novo<\/jats:italic> missense mutation hotspot in TRIO\u2019s GEF1 domain. ASD\/ID-related missense mutations within this domain compromise glutamatergic synapse function and likely contribute to the development of ASD\/ID. The number of ASD\/ID cases with mutations identified within TRIO\u2019s GEF1 domain is increasing. However, tools for accurately predicting whether such mutations are detrimental to protein function are lacking.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Here we deployed advanced protein structural modeling techniques to predict potential <jats:italic>de novo<\/jats:italic> pathogenic and benign mutations within TRIO\u2019s GEF1 domain. Mutant TRIO-9 constructs were generated and expressed in CA1 pyramidal neurons of organotypic cultured hippocampal slices. AMPA receptor-mediated postsynaptic currents were examined in these neurons using dual whole-cell patch clamp electrophysiology. We also validated these findings using orthogonal co-immunoprecipitation and fluorescence lifetime imaging (FLIM-FRET) experiments to assay TRIO mutant overexpression effects on TRIO-RAC1 binding and on RAC1 activity in HEK293\/T cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Missense mutations in TRIO\u2019s GEF1 domain that were predicted to disrupt TRIO-RAC1 binding or stability were tested experimentally and found to greatly impair TRIO-9\u2019s influence on glutamatergic synapse function. In contrast, missense mutations in TRIO\u2019s GEF1 domain that were predicted to have minimal effect on TRIO-RAC1 binding or stability did not impair TRIO-9\u2019s influence on glutamatergic synapse function in our experimental assays. In orthogonal assays, we find most of the mutations predicted to disrupt binding display loss of function but mutants predicted to disrupt stability do not reflect our results from neuronal electrophysiological data.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Limitations<\/jats:title>\n                <jats:p>We present a method to predict missense mutations in TRIO\u2019s GEF1 domain that may compromise TRIO function and test for effects in a limited number of assays. Possible limitations arising from the model systems employed here can be addressed in future studies. Our method does not provide evidence for whether these mutations confer ASD\/ID risk or the likelihood that such mutations will result in the development of ASD\/ID.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Here we show that a combination of structure-based computational predictions and experimental validation can be employed to reliably predict whether missense mutations in the human <jats:italic>TRIO<\/jats:italic> gene impede TRIO protein function and compromise TRIO\u2019s role in glutamatergic synapse regulation. With the growing accessibility of genome sequencing, the use of such tools in the accurate identification of pathological mutations will be instrumental in diagnostics of ASD\/ID.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13229-024-00590-9","type":"journal-article","created":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T23:03:14Z","timestamp":1712098994000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Detection of autism spectrum disorder-related pathogenic trio variants by a novel structure-based approach"],"prefix":"10.1186","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6859-0236","authenticated-orcid":false,"given":"Sadhna","family":"Rao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3925-983X","authenticated-orcid":false,"given":"Anastasiia","family":"Sadybekov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"DeWitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Lipka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vsevolod","family":"Katritch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce E.","family":"Herring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,3]]},"reference":[{"issue":"6","key":"590_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.ss6706a1","volume":"67","author":"J Baio","year":"2018","unstructured":"Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z, et al. Prevalence of Autism Spectrum Disorder among children aged 8 years - Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2014. MMWR Surveill Summ. 2018;67(6):1\u201323.","journal-title":"MMWR Surveill Summ"},{"issue":"10","key":"590_CR2","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1001\/jamapsychiatry.2019.1411","volume":"76","author":"D Bai","year":"2019","unstructured":"Bai D, Yip BHK, Windham GC, Sourander A, Francis R, Yoffe R, et al. Association of Genetic and Environmental Factors with Autism in a 5-Country cohort. JAMA Psychiatry. 2019;76(10):1035\u201343.","journal-title":"JAMA Psychiatry"},{"issue":"9","key":"590_CR3","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1016\/j.jaac.2018.11.017","volume":"58","author":"SN Hansen","year":"2019","unstructured":"Hansen SN, Schendel DE, Francis RW, Windham GC, Bresnahan M, Levine SZ, et al. Recurrence risk of Autism in siblings and cousins: a multinational, Population-based study. J Am Acad Child Adolesc Psychiatry. 2019;58(9):866\u201375.","journal-title":"J Am Acad Child Adolesc Psychiatry"},{"key":"590_CR4","doi-asserted-by":"publisher","first-page":"385","DOI":"10.3389\/fncel.2019.00385","volume":"13","author":"L Rylaarsdam","year":"2019","unstructured":"Rylaarsdam L, Guemez-Gamboa A. Genetic causes and modifiers of Autism Spectrum Disorder. Front Cell Neurosci. 2019;13:385.","journal-title":"Front Cell Neurosci"},{"issue":"3","key":"590_CR5","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.gde.2012.03.002","volume":"22","author":"B Devlin","year":"2012","unstructured":"Devlin B, Scherer SW. Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev. 2012;22(3):229\u201337.","journal-title":"Curr Opin Genet Dev"},{"key":"590_CR6","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1146\/annurev.genom.5.061903.180050","volume":"5","author":"J Veenstra-Vanderweele","year":"2004","unstructured":"Veenstra-Vanderweele J, Christian SL, Cook EH. Jr. Autism as a paradigmatic complex genetic disorder. Annu Rev Genomics Hum Genet. 2004;5:379\u2013405.","journal-title":"Annu Rev Genomics Hum Genet"},{"issue":"3","key":"590_CR7","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1038\/s41588-019-0344-8","volume":"51","author":"J Grove","year":"2019","unstructured":"Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H, et al. Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019;51(3):431\u201344.","journal-title":"Nat Genet"},{"issue":"1","key":"590_CR8","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/s41525-019-0093-8","volume":"4","author":"P Feliciano","year":"2019","unstructured":"Feliciano P, Zhou X, Astrovskaya I, Turner TN, Wang T, Brueggeman L, et al. Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes. npj Genomic Med. 2019;4(1):19.","journal-title":"npj Genomic Med"},{"issue":"3","key":"590_CR9","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1016\/j.cell.2019.12.036","volume":"180","author":"FK Satterstrom","year":"2020","unstructured":"Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S, An J-Y, et al. Large-scale exome sequencing study implicates both developmental and functional changes in the Neurobiology of Autism. Cell. 2020;180(3):568\u201384e23.","journal-title":"Cell"},{"issue":"2","key":"590_CR10","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.neuron.2013.01.010","volume":"77","author":"JL Stein","year":"2013","unstructured":"Stein JL, Parikshak NN, Geschwind DH. Rare inherited variation in autism: beginning to see the forest and a few trees. Neuron. 2013;77(2):209\u201311.","journal-title":"Neuron"},{"issue":"2","key":"590_CR11","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.jaac.2013.10.013","volume":"53","author":"F Volkmar","year":"2014","unstructured":"Volkmar F, Siegel M, Woodbury-Smith M, King B, McCracken J, State M. Practice parameter for the Assessment and Treatment of children and adolescents with Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2014;53(2):237\u201357.","journal-title":"J Am Acad Child Adolesc Psychiatry"},{"key":"590_CR12","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s13229-019-0284-2","volume":"10","author":"A Munnich","year":"2019","unstructured":"Munnich A, Demily C, Frugere L, Duwime C, Malan V, Barcia G, et al. Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder. Mol Autism. 2019;10:33.","journal-title":"Mol Autism"},{"key":"590_CR13","doi-asserted-by":"publisher","first-page":"594","DOI":"10.3389\/fgene.2018.00594","volume":"9","author":"X Du","year":"2018","unstructured":"Du X, Gao X, Liu X, Shen L, Wang K, Fan Y, et al. Genetic diagnostic evaluation of Trio-based whole exome sequencing among children with diagnosed or suspected Autism Spectrum Disorder. Front Genet. 2018;9:594.","journal-title":"Front Genet"},{"issue":"5","key":"590_CR14","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1097\/GIM.0b013e31804d683b","volume":"9","author":"GE Herman","year":"2007","unstructured":"Herman GE, Henninger N, Ratliff-Schaub K, Pastore M, Fitzgerald S, McBride KL. Genetic testing in autism: how much is enough? Genet Med. 2007;9(5):268\u201374.","journal-title":"Genet Med"},{"issue":"1","key":"590_CR15","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1097\/01.gim.0000195304.45116.96","volume":"8","author":"OA Abdul-Rahman","year":"2006","unstructured":"Abdul-Rahman OA, Hudgins L. The diagnostic utility of a genetics evaluation in children with pervasive developmental disorders. Genet Med. 2006;8(1):50\u20134.","journal-title":"Genet Med"},{"issue":"9","key":"590_CR16","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1097\/01.gim.0000237789.98842.f1","volume":"8","author":"GB Schaefer","year":"2006","unstructured":"Schaefer GB, Lutz RE. Diagnostic yield in the clinical genetic evaluation of autism spectrum disorders. Genet Med. 2006;8(9):549\u201356.","journal-title":"Genet Med"},{"issue":"7","key":"590_CR17","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1038\/gim.2017.166","volume":"20","author":"KS Barton","year":"2018","unstructured":"Barton KS, Tabor HK, Starks H, Garrison NA, Laurino M, Burke W. Pathways from autism spectrum disorder diagnosis to genetic testing. Genet Medicine: Official J Am Coll Med Genet. 2018;20(7):737\u201344.","journal-title":"Genet Medicine: Official J Am Coll Med Genet"},{"issue":"5","key":"590_CR18","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/gim.2013.32","volume":"15","author":"GB Schaefer","year":"2013","unstructured":"Schaefer GB, Mendelsohn NJ, for the Professional P, Guidelines C. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15(5):399\u2013407.","journal-title":"Genet Med"},{"issue":"1","key":"590_CR19","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1146\/annurev-neuro-071714-033821","volume":"38","author":"L Volk","year":"2015","unstructured":"Volk L, Chiu S-L, Sharma K, Huganir RL. Glutamate synapses in Human Cognitive disorders. Annu Rev Neurosci. 2015;38(1):127\u201349.","journal-title":"Annu Rev Neurosci"},{"issue":"1","key":"590_CR20","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1038\/s41467-017-00472-0","volume":"8","author":"A Sadybekov","year":"2017","unstructured":"Sadybekov A, Tian C, Arnesano C, Katritch V, Herring BE. An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio. Nat Commun. 2017;8(1):601.","journal-title":"Nat Commun"},{"issue":"4","key":"590_CR21","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1038\/s41380-023-01963-x","volume":"28","author":"M Bonnet","year":"2023","unstructured":"Bonnet M, Roche F, Fagotto-Kaufmann C, Gazdagh G, Truong I, Comunale F, et al. Pathogenic TRIO variants associated with neurodevelopmental disorders perturb the molecular regulation of TRIO and axon pathfinding in vivo. Mol Psychiatry. 2023;28(4):1527\u201344.","journal-title":"Mol Psychiatry"},{"issue":"3","key":"590_CR22","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1016\/j.ajhg.2020.01.018","volume":"106","author":"S Barbosa","year":"2020","unstructured":"Barbosa S, Greville-Heygate S, Bonnet M, Godwin A, Fagotto-Kaufmann C, Kajava AV, et al. Opposite modulation of RAC1 by mutations in TRIO is Associated with distinct, Domain-Specific Neurodevelopmental disorders. Am J Hum Genet. 2020;106(3):338\u201355.","journal-title":"Am J Hum Genet"},{"issue":"23","key":"590_CR23","doi-asserted-by":"publisher","first-page":"4728","DOI":"10.1093\/hmg\/ddx355","volume":"26","author":"SM Katrancha","year":"2017","unstructured":"Katrancha SM, Wu Y, Zhu M, Eipper BA, Koleske AJ, Mains RE. Neurodevelopmental disease-associated de novo mutations and rare sequence variants affect TRIO GDP\/GTP exchange factor activity. Hum Mol Genet. 2017;26(23):4728\u201340.","journal-title":"Hum Mol Genet"},{"issue":"Pt 4","key":"590_CR24","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1242\/jcs.113.4.729","volume":"113","author":"A Blangy","year":"2000","unstructured":"Blangy A, Vignal E, Schmidt S, Debant A, Gauthier-Rouvi\u00e8re C, Fort P. TrioGEF1 controls rac- and Cdc42-dependent cell structures through the direct activation of rhoG. J Cell Sci. 2000;113(Pt 4):729\u201339.","journal-title":"J Cell Sci"},{"issue":"7397","key":"590_CR25","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1038\/nature10989","volume":"485","author":"BJ O\u2019Roak","year":"2012","unstructured":"O\u2019Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485(7397):246\u201350.","journal-title":"Nature"},{"issue":"20","key":"590_CR26","doi-asserted-by":"publisher","first-page":"1921","DOI":"10.1056\/NEJMoa1206524","volume":"367","author":"J de Ligt","year":"2012","unstructured":"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(20):1921\u20139.","journal-title":"N Engl J Med"},{"issue":"7397","key":"590_CR27","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1038\/nature10945","volume":"485","author":"SJ Sanders","year":"2012","unstructured":"Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485(7397):237\u201341.","journal-title":"Nature"},{"issue":"7526","key":"590_CR28","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/nature13772","volume":"515","author":"S De Rubeis","year":"2014","unstructured":"De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515(7526):209\u201315.","journal-title":"Nature"},{"issue":"7809","key":"590_CR29","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alf\u00f6ldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434\u201343.","journal-title":"Nature"},{"issue":"3","key":"590_CR30","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1002\/(SICI)1099-1352(199905\/06)12:3<177::AID-JMR451>3.0.CO;2-Z","volume":"12","author":"M Schapira","year":"1999","unstructured":"Schapira M, Totrov M, Abagyan R. Prediction of the binding energy for small molecules, peptides and proteins. J Mol Recognit. 1999;12(3):177\u201390.","journal-title":"J Mol Recognit"},{"issue":"16","key":"590_CR31","first-page":"3041","volume":"128","author":"I Timmerman","year":"2015","unstructured":"Timmerman I, Heemskerk N, Kroon J, Schaefer A, van Rijssel J, Hoogenboezem M, et al. A local VE-cadherin and Trio-based signaling complex stabilizes endothelial junctions through Rac1. J Cell Sci. 2015;128(16):3041\u201354.","journal-title":"J Cell Sci"},{"issue":"2","key":"590_CR32","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/0165-0270(91)90128-M","volume":"37","author":"L Stoppini","year":"1991","unstructured":"Stoppini L, Buchs PA, Muller D. A simple method for organotypic cultures of nervous tissue. J Neurosci Methods. 1991;37(2):173\u201382.","journal-title":"J Neurosci Methods"},{"issue":"1","key":"590_CR33","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1006\/exnr.2001.7648","volume":"169","author":"P Prang","year":"2001","unstructured":"Prang P, Del Turco D, Kapfhammer JP. Regeneration of entorhinal fibers in mouse slice cultures is age dependent and can be stimulated by NT-4, GDNF, and modulators of G-proteins and protein kinase C. Exp Neurol. 2001;169(1):135\u201347.","journal-title":"Exp Neurol"},{"issue":"1\u20133","key":"590_CR34","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.ejphar.2009.04.007","volume":"612","author":"B Bonnici","year":"2009","unstructured":"Bonnici B, Kapfhammer JP. Modulators of signal transduction pathways can promote axonal regeneration in entorhino-hippocampal slice cultures. Eur J Pharmacol. 2009;612(1\u20133):35\u201340.","journal-title":"Eur J Pharmacol"},{"issue":"2","key":"590_CR35","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.neuron.2009.02.027","volume":"62","author":"W Lu","year":"2009","unstructured":"Lu W, Shi Y, Jackson AC, Bjorgan K, During MJ, Sprengel R, et al. Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron. 2009;62(2):254\u201368.","journal-title":"Neuron"},{"issue":"21","key":"590_CR36","doi-asserted-by":"publisher","first-page":"13902","DOI":"10.1073\/pnas.172511199","volume":"99","author":"E Schnell","year":"2002","unstructured":"Schnell E, Sizemore M, Karimzadegan S, Chen L, Bredt DS, Nicoll RA. Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc Natl Acad Sci U S A. 2002;99(21):13902\u20137.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"590_CR37","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1016\/j.jmb.2007.02.060","volume":"368","author":"MK Chhatriwala","year":"2007","unstructured":"Chhatriwala MK, Betts L, Worthylake DK, Sondek J. The DH and PH domains of Trio Coordinately Engage rho GTPases for their efficient activation. J Mol Biol. 2007;368(5):1307\u201320.","journal-title":"J Mol Biol"},{"key":"590_CR38","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1186\/1471-2105-6-134","volume":"6","author":"A Schneider","year":"2005","unstructured":"Schneider A, Cannarozzi GM, Gonnet GH. Empirical codon substitution matrix. BMC Bioinformatics. 2005;6:134.","journal-title":"BMC Bioinformatics"},{"issue":"1","key":"590_CR39","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.gene.2004.12.028","volume":"347","author":"CE McPherson","year":"2005","unstructured":"McPherson CE, Eipper BA, Mains RE. Multiple novel isoforms of Trio are expressed in the developing rat brain. Gene. 2005;347(1):125\u201335.","journal-title":"Gene"},{"key":"590_CR40","doi-asserted-by":"crossref","unstructured":"Herring BE, Nicoll RA. Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP. Proceedings of the National Academy of Sciences. 2016;113(8):2264.","DOI":"10.1073\/pnas.1600179113"},{"issue":"47","key":"590_CR41","doi-asserted-by":"publisher","first-page":"9306","DOI":"10.1523\/JNEUROSCI.1566-19.2019","volume":"39","author":"S Rao","year":"2019","unstructured":"Rao S, Kay Y, Herring BE. Tiam1 is critical for glutamatergic synapse structure and function in the Hippocampus. J Neurosci. 2019;39(47):9306.","journal-title":"J Neurosci"},{"key":"590_CR42","doi-asserted-by":"publisher","first-page":"223","DOI":"10.3389\/fnmol.2018.00223","volume":"11","author":"C Tian","year":"2018","unstructured":"Tian C, Kay Y, Sadybekov A, Rao S, Katritch V, Herring BE. An intellectual disability-related missense mutation in Rac1 prevents LTP induction. Front Mol Neurosci. 2018;11:223.","journal-title":"Front Mol Neurosci"},{"issue":"5","key":"590_CR43","doi-asserted-by":"publisher","first-page":"e1003592","DOI":"10.1371\/journal.pcbi.1003592","volume":"10","author":"N Zhao","year":"2014","unstructured":"Zhao N, Han JG, Shyu CR, Korkin D. Determining effects of non-synonymous SNPs on protein-protein interactions using supervised and semi-supervised learning. PLoS Comput Biol. 2014;10(5):e1003592.","journal-title":"PLoS Comput Biol"},{"issue":"Suppl 3","key":"590_CR44","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-2164-14-S3-S7","volume":"14","author":"F Gnad","year":"2013","unstructured":"Gnad F, Baucom A, Mukhyala K, Manning G, Zhang Z. Assessment of computational methods for predicting the effects of missense mutations in human cancers. BMC Genomics. 2013;14(Suppl 3):7.","journal-title":"BMC Genomics"},{"issue":"3","key":"590_CR45","doi-asserted-by":"publisher","first-page":"e1002886","DOI":"10.1371\/journal.pcbi.1002886","volume":"9","author":"E Khurana","year":"2013","unstructured":"Khurana E, Fu Y, Chen J, Gerstein M. Interpretation of genomic variants using a unified biological network approach. PLoS Comput Biol. 2013;9(3):e1002886.","journal-title":"PLoS Comput Biol"},{"issue":"17","key":"590_CR46","doi-asserted-by":"publisher","first-page":"e118","DOI":"10.1093\/nar\/gkr407","volume":"39","author":"B Reva","year":"2011","unstructured":"Reva B, Antipin Y, Sander C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res. 2011;39(17):e118.","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"590_CR47","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1038\/nprot.2009.86","volume":"4","author":"P Kumar","year":"2009","unstructured":"Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4(7):1073\u201381.","journal-title":"Nat Protoc"},{"issue":"6664","key":"590_CR48","doi-asserted-by":"publisher","first-page":"eadg7492","DOI":"10.1126\/science.adg7492","volume":"381","author":"J Cheng","year":"2023","unstructured":"Cheng J, Novati G, Pan J, Bycroft C, Zemgulyte A, Applebaum T, et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science. 2023;381(6664):eadg7492.","journal-title":"Science"},{"issue":"1","key":"590_CR49","doi-asserted-by":"publisher","first-page":"2180","DOI":"10.1038\/s41467-021-22369-9","volume":"12","author":"N Shemesh","year":"2021","unstructured":"Shemesh N, Jubran J, Dror S, Simonovsky E, Basha O, Argov C, et al. The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones. Nat Commun. 2021;12(1):2180.","journal-title":"Nat Commun"},{"issue":"6","key":"590_CR50","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1016\/S0896-6273(01)00427-5","volume":"31","author":"S Tobaben","year":"2001","unstructured":"Tobaben S, Thakur P, Fern\u00e1ndez-Chac\u00f3n R, S\u00fcdhof TC, Rettig J, Stahl B. A Trimeric Protein Complex Functions as a synaptic chaperone machine. Neuron. 2001;31(6):987\u201399.","journal-title":"Neuron"},{"issue":"9","key":"590_CR51","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1007\/s00439-018-1916-x","volume":"137","author":"J Weile","year":"2018","unstructured":"Weile J, Roth FP. Multiplexed assays of variant effects contribute to a growing genotype-phenotype atlas. Hum Genet. 2018;137(9):665\u201378.","journal-title":"Hum Genet"},{"issue":"3","key":"590_CR52","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.ajhg.2017.07.014","volume":"101","author":"LM Starita","year":"2017","unstructured":"Starita LM, Ahituv N, Dunham MJ, Kitzman JO, Roth FP, Seelig G, et al. Variant interpretation: functional assays to the rescue. Am J Hum Genet. 2017;101(3):315\u201325.","journal-title":"Am J Hum Genet"},{"issue":"12","key":"590_CR53","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1038\/s41588-022-01224-7","volume":"54","author":"Y Niu","year":"2022","unstructured":"Niu Y, Ferreira Azevedo CA, Li X, Kamali E, Haagen Nielsen O, Storgaard S\u00f8rensen C, et al. Multiparametric and accurate functional analysis of genetic sequence variants using CRISPR-Select. Nat Genet. 2022;54(12):1983\u201393.","journal-title":"Nat Genet"},{"issue":"7","key":"590_CR54","doi-asserted-by":"publisher","first-page":"1698","DOI":"10.1016\/j.cell.2016.05.040","volume":"165","author":"A Merk","year":"2016","unstructured":"Merk A, Bartesaghi A, Banerjee S, Falconieri V, Rao P, Davis MI, et al. Breaking Cryo-EM Resolution barriers to facilitate Drug Discovery. Cell. 2016;165(7):1698\u2013707.","journal-title":"Cell"},{"issue":"7620","key":"590_CR55","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1038\/nature19948","volume":"537","author":"R Fernandez-Leiro","year":"2016","unstructured":"Fernandez-Leiro R, Scheres SHW. Unravelling biological macromolecules with cryo-electron microscopy. Nature. 2016;537(7620):339\u201346.","journal-title":"Nature"},{"issue":"9","key":"590_CR56","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/j.tibs.2017.06.007","volume":"42","author":"LC Johansson","year":"2017","unstructured":"Johansson LC, Stauch B, Ishchenko A, Cherezov V. A Bright Future for serial femtosecond crystallography with XFELs. Trends Biochem Sci. 2017;42(9):749\u201362.","journal-title":"Trends Biochem Sci"},{"key":"590_CR57","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1007\/978-1-61779-276-2_19","volume":"781","author":"B Webb","year":"2011","unstructured":"Webb B, Lasker K, Schneidman-Duhovny D, Tjioe E, Phillips J, Kim SJ, et al. Modeling of proteins and their assemblies with the integrative modeling platform. Methods Mol Biol. 2011;781:377\u201397.","journal-title":"Methods Mol Biol"},{"issue":"7792","key":"590_CR58","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1038\/s41586-019-1923-7","volume":"577","author":"AW Senior","year":"2020","unstructured":"Senior AW, Evans R, Jumper J, Kirkpatrick J, Sifre L, Green T, et al. Improved protein structure prediction using potentials from deep learning. Nature. 2020;577(7792):706\u201310.","journal-title":"Nature"}],"container-title":["Molecular Autism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13229-024-00590-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13229-024-00590-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13229-024-00590-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T23:03:51Z","timestamp":1712099031000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularautism.biomedcentral.com\/articles\/10.1186\/s13229-024-00590-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,3]]},"references-count":58,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["590"],"URL":"https:\/\/doi.org\/10.1186\/s13229-024-00590-9","relation":{},"ISSN":["2040-2392"],"issn-type":[{"value":"2040-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,3]]},"assertion":[{"value":"19 December 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 April 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All experimental procedures were carried out in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and approved by the University of Southern California Institutional Animal Care and Use Committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12"}}