{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:52:02Z","timestamp":1789710722358,"version":"4.0.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>\n                    <jats:bold>Objective:<\/jats:bold>\n                    To prove microtubule associated serine\/threonine kinase 3 (\n                    <jats:italic>MAST3<\/jats:italic>\n                    ) gene is associated with neurodevelopmental diseases (NDD) and the genotype-phenotype correlation.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    Trio exome sequencing (trio ES) was performed on four NDD trios. Bioinformatic analysis was conducted based on large-scale genome sequencing data and human brain transcriptomic data. Further\n                    <jats:italic>in vivo<\/jats:italic>\n                    zebrafish studies were performed.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    In our study, we identified four\n                    <jats:italic>de novo MAST3<\/jats:italic>\n                    variants (NM_015016.1: c.302C &amp;gt; T:p.Ser101Phe; c.311C &amp;gt; T:p.Ser104Leu; c.1543G &amp;gt; A:p.Gly515Ser; and c.1547T &amp;gt; C:p.Leu516Pro) in four patients with developmental and epileptic encephalopathy (DEE) separately. Clinical heterogeneities were observed in patients carrying variants in domain of unknown function (DUF) and serine-threonine kinase (STK) domain separately. Using the published large-scale exome sequencing data, higher CADD scores of missense variants in DUF domain were found in NDD cohort compared with gnomAD database. In addition, we obtained an excess of missense variants in DUF domain when compared autistic spectrum disorder (ASD) cohort with gnomAD database, similarly an excess of missense variants in STK domain when compared DEE cohort with gnomAD database. Based on Brainspan datasets, we showed that\n                    <jats:italic>MAST3<\/jats:italic>\n                    expression was significantly upregulated in ASD and DEE-related brain regions and was functionally linked with DEE genes. In zebrafish model, abnormal morphology of central nervous system was observed in\n                    <jats:italic>mast3a\/b<\/jats:italic>\n                    crispants.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusion:<\/jats:bold>\n                    Our results support the possibility that\n                    <jats:italic>MAST3<\/jats:italic>\n                    is a novel gene associated with NDD which could expand the genetic spectrum for NDD. The genotype-phenotype correlation may contribute to future genetic counseling.\n                  <\/jats:p>","DOI":"10.3389\/fnmol.2021.775479","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T13:24:54Z","timestamp":1641993894000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["The Role of Microtubule Associated Serine\/Threonine Kinase 3 Variants in Neurodevelopmental Diseases: Genotype-Phenotype Association"],"prefix":"10.3389","volume":"14","author":[{"given":"Li","family":"Shu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neng","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiong","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanghui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoxian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinrui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyue","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengchao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3791\/4196","article-title":"Regular care and maintenance of a zebrafish (Danio rerio) laboratory: an introduction.","volume":"18","author":"Avdesh","year":"2012","journal-title":"J. Vis. Exp."},{"key":"B2","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1007\/s12031-019-01415-8","article-title":"Evaluating the role of MAST1 as an intellectual disability disease gene: identification of a novel De Novo variant in a patient with developmental disabilities.","volume":"70","author":"Ben-Mahmoud","year":"2020","journal-title":"J. Mol. Neurosci."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1001046","article-title":"A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice.","volume":"6","author":"Boumil","year":"2010","journal-title":"PLoS Genet."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01281-0","article-title":"IQSEC2 mutation associated with epilepsy, intellectual disability, and autism results in hyperexcitability of patient-derived neurons and deficient synaptic transmission.","volume":"12","author":"Brant","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku936","article-title":"Easy quantitative assessment of genome editing by sequence trace decomposition.","volume":"42","author":"Brinkman","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1042\/BJ20141198","article-title":"Deciphering the unconventional peptide binding to the PDZ domain of MAST2.","volume":"469","author":"Delhommel","year":"2015","journal-title":"Biochem. J."},{"key":"B7","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1093\/genetics\/151.4.1531","article-title":"Preservation of duplicate genes by complementary, degenerative mutations.","volume":"151","author":"Force","year":"1999","journal-title":"Genetics"},{"key":"B8","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.brainres.2007.12.027","article-title":"Expression of the MAST family of serine\/threonine kinases.","volume":"1195","author":"Garland","year":"2008","journal-title":"Brain Res."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0151148","article-title":"Epilepsy, behavioral abnormalities, and physiological comorbidities in syntaxin-binding protein 1 (STXBP1) mutant zebrafish.","volume":"11","author":"Grone","year":"2016","journal-title":"PLoS One"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2119","DOI":"10.1242\/dev.104711","article-title":"The Drosophila MAST kinase drop out is required to initiate membrane compartmentalisation during cellularisation and regulates dynein-based transport.","volume":"141","author":"Hain","year":"2014","journal-title":"Development"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1038\/s41588-018-0143-7","article-title":"De novo variants in neurodevelopmental disorders with epilepsy.","volume":"50","author":"Heyne","year":"2018","journal-title":"Nat. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1038\/ejhg.2013.114","article-title":"Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly.","volume":"22","author":"Hobert","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1016\/j.ajhg.2019.07.005","article-title":"De Novo missense variants in FBXW11 cause diverse developmental phenotypes including brain, eye, and digit anomalies.","volume":"105","author":"Holt","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/nature12111","article-title":"The zebrafish reference genome sequence and its relationship to the human genome.","volume":"496","author":"Howe","year":"2013","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2020.107686","article-title":"Mechanisms of cognitive impairment in temporal lobe epilepsy: a systematic review of resting-state functional connectivity studies.","volume":"115","author":"Ives-Deliperi","year":"2021","journal-title":"Epilepsy Behav."},{"key":"B16","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1136\/jmedgenet-2018-105775","article-title":"Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing.","volume":"56","author":"Iwama","year":"2019","journal-title":"J. Med. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.neubiorev.2021.04.014","article-title":"Meta-analytic evidence of differential prefrontal and early sensory cortex activity during non-social sensory perception in autism.","volume":"127","author":"Jassim","year":"2021","journal-title":"Neurosci. Biobehav. Rev."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1002\/2211-5463.12860","article-title":"MAST1 modulates neuronal differentiation and cell cycle exit via P27 in neuroblastoma cells.","volume":"10","author":"Jing","year":"2020","journal-title":"FEBS Open Bio."},{"key":"B19","doi-asserted-by":"publisher","first-page":"13755","DOI":"10.1074\/jbc.RA119.008238","article-title":"Structure-based optimization of a PDZ-binding motif within a viral peptide stimulates neurite outgrowth.","volume":"294","author":"Khan","year":"2019","journal-title":"J. Biol. Chem."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0040029","article-title":"Subfunctionalization of duplicated zebrafish pax6 genes by cis-regulatory divergence.","volume":"4","author":"Kleinjan","year":"2008","journal-title":"PLoS Genet."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-020-00725-6","article-title":"Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders.","volume":"12","author":"Lal","year":"2020","journal-title":"Genome Med."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-15-26","article-title":"Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening.","volume":"15","author":"Marchese","year":"2014","journal-title":"BMC Med. Genet."},{"key":"B23","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1038\/mp.2014.189","article-title":"Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy.","volume":"20","author":"McMichael","year":"2015","journal-title":"Mol. Psychiatry"},{"key":"B24","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1016\/s0955-0674(99)00039-3","article-title":"Gene and genome duplications in vertebrates: the one-to-four (-to-eight in fish) rule and the evolution of novel gene functions.","volume":"11","author":"Meyer","year":"1999","journal-title":"Curr. Opin. Cell Biol."},{"key":"B25","year":"2011","journal-title":"Guide for the Care and Use of Laboratory Animals"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1619","DOI":"10.1126\/science.1227764","article-title":"Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.","volume":"338","author":"O\u2019Roak","year":"2012","journal-title":"Science"},{"key":"B27","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1006\/dbio.2000.9898","article-title":"Analysis of upstream elements in the HuC promoter leads to the establishment of transgenic zebrafish with fluorescent neurons.","volume":"227","author":"Park","year":"2000","journal-title":"Dev. Biol."},{"key":"B28","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1002\/ajmg.a.61560","article-title":"MAST1 variant causes mega-corpus-callosum syndrome with cortical malformations but without cerebellar hypoplasia.","volume":"182","author":"Rodriguez-Garcia","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"B29","doi-asserted-by":"publisher","first-page":"7795","DOI":"10.1073\/pnas.85.20.7795","article-title":"Convulsant-induced increase in transcription factor messenger RNAs in rat brain.","volume":"85","author":"Saffen","year":"1988","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B30","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1242\/dmm.009779","article-title":"Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development.","volume":"5","author":"Shin","year":"2012","journal-title":"Dis. Model. Mech."},{"key":"B31","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1006\/geno.1996.0506","article-title":"Assignment of the human syntaxin 1B gene (STX) to chromosome 16p11.2 by fluorescence in situ hybridization.","volume":"36","author":"Smirnova","year":"1996","journal-title":"Genomics"},{"key":"B32","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1002\/ana.26147","article-title":"Pathogenic MAST3 variants in the STK domain are associated with epilepsy.","volume":"90","author":"Spinelli","year":"2021","journal-title":"Ann. Neurol."},{"key":"B33","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1016\/j.neuron.2018.10.044","article-title":"Mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations.","volume":"100","author":"Tripathy","year":"2018","journal-title":"Neuron"},{"key":"B34","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/978-1-4939-8876-1_21","article-title":"Bioinformatics analysis of whole exome sequencing data.","volume":"1881","author":"Ulintz","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"28936","DOI":"10.1074\/jbc.M504761200","article-title":"Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine\/threonine kinases.","volume":"280","author":"Valiente","year":"2005","journal-title":"J. Biol. Chem."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"B37","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/S0896-6273(00)80588-7","article-title":"Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins.","volume":"21","author":"Xiao","year":"1998","journal-title":"Neuron"}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2021.775479\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T13:25:00Z","timestamp":1641993900000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2021.775479\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,12]]},"references-count":37,"alternative-id":["10.3389\/fnmol.2021.775479"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2021.775479","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,12]]},"article-number":"775479"}}