{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T21:14:43Z","timestamp":1788556483194,"version":"build-2803163510"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"18","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":246,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Autism Spectrum Program of Excellence"},{"name":"Simons Foundation Bridge to Independence award"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R56MH096881"],"award-info":[{"award-number":["R56MH096881"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM146782"],"award-info":[{"award-number":["R35GM146782"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Heterozygous deletions in NRXN1, encoding the presynaptic adhesion molecule Neurexin 1, are among the most frequently identified rare variants in schizophrenia and other neuropsychiatric disorders. Patient sequencing has revealed that 3\u2032 deletions within NRXN1 generate novel isoforms not produced from the intact locus, yet whether these isoforms are functional, passively non-functional, or actively pathogenic in vivo is still not clear. To address this, we expressed eight human NRXN1 isoforms in C. elegans neurons including four control isoforms and four 3\u2032 deletion variant isoforms identified in schizophrenia patient cell lines, and characterized their effects on protein localization and two independent behaviors: a food deprivation response and social feeding behaviors. Most human isoforms showed expression and localization within the nerve ring and neurons similar to the C. elegans ortholog, NRX-1; however, several isoforms, particularly among the 3\u2032 deletion variants, displayed aberrant accumulation in neuronal cell bodies or as puncta in neuropil. Functionally, isoforms fell into one of three categories: no effect on nrx-1 loss-of-function behavioral phenotypes, partial rescue, or gain of function, with multiple isoforms showing differences between the behaviors. Strikingly, two 3\u2032 deletion isoforms produced gain-of-function behavioral phenotypes more severe than the nrx-1 null mutant, demonstrating that these patient-derived variants can be actively pathogenic. These results establish C. elegans as a tractable in vivo platform for dissecting the isoform-specific functional consequences of NRXN1 variants and suggest that strategies for NRXN1-associated neuropsychiatric diseases must account for both loss-of-function and gain-of-function isoform mechanisms.<\/jats:p>","DOI":"10.1093\/hmg\/ddag085","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:38:25Z","timestamp":1787657905000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>In vivo<\/i>\n                    dissection of human\n                    <i>NRXN1<\/i>\n                    isoforms reveals gain-of-function pathogenicity of schizophrenia-associated 3\u2032 deletions"],"prefix":"10.1093","volume":"35","author":[{"given":"Dustin","family":"Haskell","sequence":"first","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, 415 Curie Blvd, Philadelphia PA 19146, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8865-3062","authenticated-orcid":false,"given":"Michael P","family":"Hart","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, 415 Curie Blvd, Philadelphia PA 19146, USA"},{"name":"Autism Spectrum Program of Excellence, Perelman School of Medicine, 415 Curie Blvd, Philadelphia PA 19146, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"2026090416443065800_ref1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.neuron.2023.10.037","article-title":"An evolutionary perspective on complex neuropsychiatric disease","volume":"112","author":"McClellan","year":"2024","journal-title":"Neuron"},{"key":"2026090416443065800_ref2","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1002\/ajmg.c.31327","article-title":"The genetic variability and commonality of neurodevelopmental disease","volume":"160C","author":"Coe","year":"2012","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"2026090416443065800_ref3","doi-asserted-by":"publisher","first-page":"e1008922","DOI":"10.1371\/journal.pgen.1008922","article-title":"Unified inference of missense variant effects and gene constraints in the human genome","volume":"16","author":"Huang","year":"2020","journal-title":"PLoS Genet"},{"key":"2026090416443065800_ref4","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1016\/j.bpsc.2018.03.015","article-title":"Understanding the emergence of neuropsychiatric disorders with network neuroscience","volume":"3","author":"Bassett","year":"2018","journal-title":"Biol Psychiatry Cogn Neurosci Neuroimaging"},{"key":"2026090416443065800_ref5","doi-asserted-by":"crossref","first-page":"2398212818799271","DOI":"10.1177\/2398212818799271","article-title":"The genetics of neuropsychiatric disorders","volume":"2","author":"Bray","year":"2019","journal-title":"Brain Neurosci Adv"},{"key":"2026090416443065800_ref6","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/s41588-018-0059-2","article-title":"Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection","volume":"50","author":"Pardi\u00f1as","year":"2018","journal-title":"Nat Genet"},{"key":"2026090416443065800_ref7","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1007\/s00406-020-01158-3","article-title":"Genetic risks of schizophrenia identified in a matched case-control study","volume":"271","author":"Oishi","year":"2021","journal-title":"Eur Arch Psychiatry Clin Neurosci"},{"key":"2026090416443065800_ref8","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1038\/s41586-022-04434-5","article-title":"Mapping genomic loci implicates genes and synaptic biology in schizophrenia","volume":"604","author":"Trubetskoy","year":"2022","journal-title":"Nature"},{"key":"2026090416443065800_ref9","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.cell.2019.01.015","article-title":"Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders","volume":"177","author":"Sullivan","year":"2019","journal-title":"Cell"},{"key":"2026090416443065800_ref10","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1126\/science.abi8206","article-title":"Discovery and implications of polygenicity of common disease","volume":"373","author":"Visscher","year":"2021","journal-title":"Science"},{"key":"2026090416443065800_ref11","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1002\/wps.21034","article-title":"New insights from the last decade of research in psychiatric genetics: discoveries, challenges and clinical implications","volume":"22","author":"Andreassen","year":"2023","journal-title":"World Psychiatry"},{"key":"2026090416443065800_ref12","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/s41398-024-02866-3","article-title":"Genetic and phenotypic similarity across major psychiatric disorders: a systematic review and quantitative assessment","volume":"14","author":"Bourque","year":"2024","journal-title":"Transl Psychiatry"},{"key":"2026090416443065800_ref13","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/s41583-020-00415-7","article-title":"Neurexins: molecular codes for shaping neuronal synapses","volume":"22","author":"Gomez","year":"2021","journal-title":"Nat Rev Neurosci"},{"key":"2026090416443065800_ref14","doi-asserted-by":"publisher","first-page":"101983","DOI":"10.1016\/j.pneurobio.2020.101983","article-title":"Proper synaptic adhesion signaling in the control of neural circuit architecture and brain function","volume":"200","author":"Kim","year":"2021","journal-title":"Prog Neurobiol"},{"key":"2026090416443065800_ref15","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.cell.2017.10.024","article-title":"Synaptic neurexin complexes: a molecular code for the logic of neural circuits","volume":"171","author":"S\u00fcdhof","year":"2017","journal-title":"Cell"},{"key":"2026090416443065800_ref16","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1126\/science.1621094","article-title":"Neurexins: synaptic cell surface proteins related to the alpha-latrotoxin receptor and laminin","volume":"257","author":"Ushkaryov","year":"1992","journal-title":"Science"},{"key":"2026090416443065800_ref17","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1186\/gb-2013-14-9-213","article-title":"Neurexins","volume":"14","author":"Reissner","year":"2013","journal-title":"Genome Biol"},{"key":"2026090416443065800_ref18","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/0896-6273(95)90306-2","article-title":"Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons","volume":"14","author":"Ullrich","year":"1995","journal-title":"Neuron"},{"key":"2026090416443065800_ref19","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1006\/geno.2002.6780","article-title":"Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing","volume":"79","author":"Tabuchi","year":"2002","journal-title":"Genomics"},{"key":"2026090416443065800_ref20","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1007\/s12035-011-8213-1","article-title":"Neurexins and neuroligins: recent insights from invertebrates","volume":"44","author":"Knight","year":"2011","journal-title":"Mol Neurobiol"},{"key":"2026090416443065800_ref21","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.neuron.2018.09.007","article-title":"\u0393-Neurexin and frizzled mediate parallel synapse assembly pathways antagonized by receptor endocytosis","volume":"100","author":"Kurshan","year":"2018","journal-title":"Neuron"},{"key":"2026090416443065800_ref22","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1016\/j.str.2010.06.005","article-title":"The macromolecular architecture of the extracellular domain of \u03b1NRXN1: domain organization, flexibility, and insights into trans-synaptic disposition","volume":"18","author":"Comoletti","year":"2010","journal-title":"Structure"},{"key":"2026090416443065800_ref23","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1038\/nn1074","article-title":"Neurexin mediates the assembly of presynaptic terminals","volume":"6","author":"Dean","year":"2003","journal-title":"Nat Neurosci"},{"key":"2026090416443065800_ref24","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/S0092-8674(00)80877-6","article-title":"Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons","volume":"101","author":"Scheiffele","year":"2000","journal-title":"Cell"},{"key":"2026090416443065800_ref25","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.neuroscience.2005.11.040","article-title":"Alpha-neurexins are required for efficient transmitter release and synaptic homeostasis at the mouse neuromuscular junction","volume":"138","author":"Sons","year":"2006","journal-title":"Neuroscience"},{"key":"2026090416443065800_ref26","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/j.neuron.2010.04.008","article-title":"Neurexins physically and functionally interact with GABA(a) receptors","volume":"66","author":"Zhang","year":"2010","journal-title":"Neuron"},{"key":"2026090416443065800_ref27","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1038\/nature01755","article-title":"Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis","volume":"423","author":"Missler","year":"2003","journal-title":"Nature"},{"key":"2026090416443065800_ref28","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/nrn.2015.3","article-title":"Specification of synaptic connectivity by cell surface interactions","volume":"17","author":"Wit","year":"2016","journal-title":"Nat Rev Neurosci"},{"key":"2026090416443065800_ref29","doi-asserted-by":"publisher","first-page":"e22757","DOI":"10.7554\/eLife.22757","article-title":"An alternative splicing switch shapes neurexin repertoires in principal neurons versus interneurons in the mouse hippocampus","volume":"5","author":"Nguyen","year":"2016","journal-title":"eLife"},{"key":"2026090416443065800_ref30","doi-asserted-by":"publisher","first-page":"E1291","DOI":"10.1073\/pnas.1403244111","article-title":"Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing","volume":"111","author":"Treutlein","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026090416443065800_ref31","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/j.neuron.2014.09.011","article-title":"Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins","volume":"84","author":"Schreiner","year":"2014","journal-title":"Neuron"},{"key":"2026090416443065800_ref32","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.neuron.2010.06.001","article-title":"Splice form dependence of beta-neurexin\/neuroligin binding interactions","volume":"67","author":"Koehnke","year":"2010","journal-title":"Neuron"},{"key":"2026090416443065800_ref33","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1016\/j.neuron.2017.06.010","article-title":"Rare copy number variants in NRXN1 and CNTN6 increase risk for Tourette syndrome","volume":"94","author":"Huang","year":"2017","journal-title":"Neuron"},{"key":"2026090416443065800_ref34","doi-asserted-by":"publisher","first-page":"7436","DOI":"10.1038\/s41380-021-01190-2","article-title":"Neurexin 1 variants as risk factors for suicide death","volume":"26","author":"William","year":"2021","journal-title":"Mol Psychiatry"},{"key":"2026090416443065800_ref35","doi-asserted-by":"publisher","first-page":"100356","DOI":"10.1016\/j.xgen.2023.100356","article-title":"Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions","volume":"3","author":"Maury","year":"2023","journal-title":"Cell Genom"},{"key":"2026090416443065800_ref36","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1111\/cge.13537","article-title":"Phenotypic spectrum of NRXN1 mono- and bi-allelic deficiency: a systematic review","volume":"97","author":"Castronovo","year":"2020","journal-title":"Clin Genet"},{"key":"2026090416443065800_ref37","doi-asserted-by":"publisher","first-page":"2067","DOI":"10.3390\/jcm13072067","article-title":"Landscape of NRXN1 gene variants in phenotypic manifestations of autism Spectrum disorder: a systematic review","volume":"13","author":"Cooper","year":"2024","journal-title":"J Clin Med"},{"key":"2026090416443065800_ref38","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1038\/s41586-025-08864-9","article-title":"Phenotypic complexities of rare heterozygous neurexin-1 deletions","volume":"642","author":"Fernando","year":"2025","journal-title":"Nature"},{"key":"2026090416443065800_ref39","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/s41398-023-02668-z","article-title":"Distinct neurexin isoforms cooperate to initiate and maintain foraging activity","volume":"13","author":"Bastien","year":"2023","journal-title":"Transl Psychiatry"},{"key":"2026090416443065800_ref40","doi-asserted-by":"publisher","first-page":"9301","DOI":"10.1038\/s41467-024-53590-x","article-title":"Conserved autism-associated genes tune social feeding behavior in C. Elegans","volume":"15","author":"Cowen","year":"2024","journal-title":"Nat Commun"},{"key":"2026090416443065800_ref41","doi-asserted-by":"crossref","first-page":"e0229583","DOI":"10.1371\/journal.pone.0229583","article-title":"Optimized criteria for locomotion-based healthspan evaluation in C. Elegans using the WorMotel system","volume":"15","author":"Jushaj","year":"2020","journal-title":"PLoS One"},{"key":"2026090416443065800_ref42","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/S0092-8674(00)81609-8","article-title":"Natural variation in a neuropeptide Y receptor homolog modifies social behavior and food response in C. Elegans","volume":"94","author":"De Bono","year":"1998","journal-title":"Cell"},{"key":"2026090416443065800_ref43","doi-asserted-by":"publisher","first-page":"1679","DOI":"10.1038\/s41588-019-0539-z","article-title":"Neuronal impact of patient-specific aberrant NRXN1\u03b1 splicing","volume":"51","author":"Flaherty","year":"2019","journal-title":"Nat Genet"},{"key":"2026090416443065800_ref44","doi-asserted-by":"publisher","first-page":"jkae111","DOI":"10.1093\/g3journal\/jkae111","article-title":"Neurexin drives Caenorhabditis elegans avoidance behavior independently of its post-synaptic binding partner neuroligin","volume":"14","author":"Muirhead","year":"2024","journal-title":"G3 Genes Genomes Genet"},{"key":"2026090416443065800_ref45","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1093\/genetics\/77.1.71","article-title":"The genetics of Caenorhabditis elegans","volume":"77","author":"Brenner","year":"1974","journal-title":"Genetics"},{"key":"2026090416443065800_ref46","doi-asserted-by":"publisher","first-page":"e26652","DOI":"10.7554\/eLife.26652","article-title":"Longitudinal imaging of Caenorhabditis elegans in a microfabricated device reveals variation in behavioral decline during aging","volume":"6","author":"Churgin","year":"2017","journal-title":"eLife"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/35\/18\/ddag085\/70965113\/ddag085.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/35\/18\/ddag085\/70965113\/ddag085.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T20:44:40Z","timestamp":1788554680000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/doi\/10.1093\/hmg\/ddag085\/8785973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":46,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2026,8,25]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddag085","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2026]]},"article-number":"ddag085"}}