{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:05:33Z","timestamp":1789416333706,"version":"build-2803163510"},"reference-count":90,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T00:00:00Z","timestamp":1692316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Julie Bonasera Fund for ALS and Neuromuscular Diseases"},{"name":"William White Family Fund for ALS"},{"name":"Barbara J. and James S. Greetham Jr Fund in Memory of Mark Allan Schuler"},{"name":"Ohio State Neurological Institute"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Single-nucleotide variants (SNVs) in the gene encoding Kinesin Family Member 5A (KIF5A), a neuronal motor protein involved in anterograde transport along microtubules, have been associated with amyotrophic lateral sclerosis (ALS). ALS is a rapidly progressive and fatal neurodegenerative disease that primarily affects the motor neurons. Numerous ALS-associated KIF5A SNVs are clustered near the splice-site junctions of the penultimate exon 27 and are predicted to alter the carboxy-terminal (C-term) cargo-binding domain of KIF5A. Mis-splicing of exon 27, resulting in exon exclusion, is proposed to be the mechanism by which these SNVs cause ALS. Whether all SNVs proximal to exon 27 result in exon exclusion is unclear. To address this question, we designed an in vitro minigene splicing assay in human embryonic kidney 293 cells, which revealed heterogeneous site-specific effects on splicing: only 5\u2032 splice-site (5\u2019ss) SNVs resulted in exon skipping. We also quantified splicing in select clustered, regularly interspaced, short palindromic repeats-edited human stem cells, differentiated to motor neurons, and in neuronal tissues from a 5\u2019ss SNV knock-in mouse, which showed the same result. Moreover, the survival of representative 3\u2032 splice site, 5\u2019ss, and truncated C-term variant KIF5A (v-KIF5A) motor neurons was severely reduced compared with wild-type motor neurons, and overt morphological changes were apparent. While the total KIF5A mRNA levels were comparable across the cell lines, the total KIF5A protein levels were decreased for v-KIF5A lines, suggesting an impairment of protein synthesis or stability. Thus, despite the heterogeneous effect on ribonucleic acid splicing, KIF5A SNVs similarly reduce the availability of the KIF5A protein, leading to axonal transport defects and motor neuron pathology.<\/jats:p>","DOI":"10.1093\/hmg\/ddad134","type":"journal-article","created":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T09:41:04Z","timestamp":1692351664000},"page":"3166-3180","source":"Crossref","is-referenced-by-count":8,"title":["Heterogeneous splicing patterns resulting from <i>KIF5A<\/i> variants associated with amyotrophic lateral sclerosis"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9494-6483","authenticated-orcid":false,"given":"Megan G","family":"Pino","sequence":"first","affiliation":[{"name":"Department of Neurology, The Ohio State University Wexner Medical Center , Columbus, OH 43210 , United States"},{"name":"Center for RNA Biology, The Ohio State University , Columbus, OH 43210 , United States"},{"name":"Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center , Columbus, OH 43210 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly A","family":"Rich","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Ohio State University Wexner Medical Center , Columbus, OH 43210 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Ohio State University Wexner Medical Center , Columbus, OH 43210 , United States"},{"name":"Center for RNA Biology, The Ohio State University , Columbus, OH 43210 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith L","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Ohio State University Wexner Medical Center , Columbus, OH 43210 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Ohio State University Wexner Medical Center , Columbus, OH 43210 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Musier-Forsyth","sequence":"additional","affiliation":[{"name":"Center for RNA Biology, The Ohio State University , Columbus, OH 43210 , United States"},{"name":"Department of Chemistry & Biochemistry, The Ohio State University Wexner Medical Center , Columbus, OH 43210 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8503-8459","authenticated-orcid":false,"given":"Stephen J","family":"Kolb","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Ohio State University Wexner Medical Center , Columbus, OH 43210 , United States"},{"name":"Center for RNA Biology, The Ohio State University , Columbus, OH 43210 , United States"},{"name":"Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center , Columbus, OH 43210 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,8,18]]},"reference":[{"key":"2023110804130084900_ref1","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1146\/annurev.biochem.72.121801.161720","article-title":"Mechanisms of alternative pre-messenger RNA splicing","volume":"72","author":"Black","year":"2003","journal-title":"Annu Rev Biochem"},{"key":"2023110804130084900_ref2","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1101\/gad.1048803","article-title":"Pre-mRNA splicing and human disease","volume":"17","author":"Faustino","year":"2003","journal-title":"Genes Dev"},{"key":"2023110804130084900_ref3","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/nbt964","article-title":"Alternative splicing in disease and therapy","volume":"22","author":"Garcia-Blanco","year":"2004","journal-title":"Nat Biotechnol"},{"key":"2023110804130084900_ref4","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/S0168-9525(01)02626-9","article-title":"Alternative splicing: multiple control mechanisms and involvement in human disease","volume":"18","author":"C\u00e1ceres","year":"2002","journal-title":"Trends Genet"},{"key":"2023110804130084900_ref5","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1126\/science.aad9417","article-title":"RNA splicing is a primary link between genetic variation and disease","volume":"352","author":"Li","year":"2016","journal-title":"Science"},{"key":"2023110804130084900_ref6","doi-asserted-by":"crossref","first-page":"11093","DOI":"10.1073\/pnas.1101135108","article-title":"Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes","volume":"108","author":"Lim","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023110804130084900_ref7","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.tig.2018.10.002","article-title":"RNA splicing and disease: animal models to therapies","volume":"35","author":"Montes","year":"2019","journal-title":"Trends Genet"},{"key":"2023110804130084900_ref8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/BF00210743","article-title":"The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences","volume":"90","author":"Krawczak","year":"1992","journal-title":"Hum Genet"},{"key":"2023110804130084900_ref9","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/83759","article-title":"The power of point mutations","volume":"27","author":"Maquat","year":"2001","journal-title":"Nat Genet"},{"key":"2023110804130084900_ref10","doi-asserted-by":"crossref","first-page":"E173","DOI":"10.1002\/humu.20826","article-title":"Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations","volume":"29","author":"Pros","year":"2008","journal-title":"Hum Mutat"},{"key":"2023110804130084900_ref11","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1080\/15257770.2021.1880009","article-title":"Missense, silent, non-sense and frame-shift mutations in exon 3 of the filaggrin gene in patients with bronchial asthma, atopic dermatitis, allergic rhinitis and mixed atopy","volume":"40","author":"Salama","year":"2021","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"2023110804130084900_ref12","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.3390\/ijms23052762","article-title":"The molecular basis of FIX deficiency in hemophilia B","volume":"23","author":"Shen","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2023110804130084900_ref13","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1146\/annurev-biochem-060614-034316","article-title":"Mechanisms and regulation of alternative pre-mRNA splicing","volume":"84","author":"Lee","year":"2015","journal-title":"Annu Rev Biochem"},{"key":"2023110804130084900_ref14","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/wrna.1158","article-title":"Targeting RNA splicing for disease therapy","volume":"4","author":"Havens","year":"2013","journal-title":"Wiley Interdiscip Rev RNA"},{"key":"2023110804130084900_ref15","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/bies.950150905","article-title":"The spliceosome","volume":"15","author":"Lamond","year":"1993","journal-title":"BioEssays"},{"key":"2023110804130084900_ref16","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/S0092-8674(00)81057-0","article-title":"A novel spliceosome containing U11, U12, and U5 snRNPs excises a minor class (AT-AC) intron in vitro","volume":"84","author":"Tarn","year":"1996","journal-title":"Cell"},{"key":"2023110804130084900_ref17","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/S0955-0674(00)00097-1","article-title":"Mechanisms of fidelity in pre-mRNA splicing","volume":"12","author":"Reed","year":"2000","journal-title":"Curr Opin Cell Biol"},{"key":"2023110804130084900_ref18","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1261\/rna.2040605","article-title":"Determinants of the inherent strength of human 5\u2032 splice sites","volume":"11","author":"Roca","year":"2005","journal-title":"RNA"},{"key":"2023110804130084900_ref19","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1101\/gr.6859308","article-title":"Features of 5\u2032-splice-site efficiency derived from disease-causing mutations and comparative genomics","volume":"18","author":"Roca","year":"2008","journal-title":"Genome Res"},{"key":"2023110804130084900_ref20","doi-asserted-by":"crossref","first-page":"603023","DOI":"10.3389\/fnins.2020.603023","article-title":"Searching far and genome-wide: the relevance of association studies in amyotrophic lateral sclerosis","volume":"14","author":"Rich","year":"2020","journal-title":"Front Neurosci"},{"key":"2023110804130084900_ref21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10571-019-00717-0","article-title":"Alternative splicing of ALS genes: misregulation and potential therapies","volume":"40","author":"Perrone","year":"2020","journal-title":"Cell Mol Neurobiol"},{"key":"2023110804130084900_ref22","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.3389\/fnins.2019.01310","article-title":"ALS genetics, mechanisms, and therapeutics: Where are we now?","volume":"13","author":"Mejzini","year":"2019","journal-title":"Front Neurosci"},{"key":"2023110804130084900_ref23","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1002\/ana.410180302","article-title":"Amyotrophic lateral sclerosis: part 1. Clinical features, pathology, and ethical issues in management","volume":"18","author":"Tandan","year":"1985","journal-title":"Ann Neurol"},{"key":"2023110804130084900_ref24","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1159\/000516752","article-title":"Estimated prevalence and incidence of amyotrophic lateral sclerosis and SOD1 and C9orf72 genetic variants","volume":"55","author":"Brown","year":"2021","journal-title":"Neuroepidemiology"},{"key":"2023110804130084900_ref25","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1097\/WCO.0000000000000730","article-title":"Epidemiology of amyotrophic lateral sclerosis: an update of recent literature","volume":"32","author":"Longinetti","year":"2019","journal-title":"Curr Opin Neurol"},{"key":"2023110804130084900_ref26","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1212\/WNL.36.4.511","article-title":"Familial adult motor neuron disease: amyotrophic lateral sclerosis","volume":"36","author":"Mulder","year":"1986","journal-title":"Neurology"},{"key":"2023110804130084900_ref27","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1007\/s00415-019-09652-y","article-title":"Global variation in prevalence and incidence of amyotrophic lateral sclerosis: a systematic review and meta-analysis","volume":"267","author":"Xu","year":"2020","journal-title":"J Neurol"},{"key":"2023110804130084900_ref28","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.neuron.2010.09.039","article-title":"Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease","volume":"68","author":"Hirokawa","year":"2010","journal-title":"Neuron"},{"key":"2023110804130084900_ref29","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nrn1624","article-title":"Molecular motors and mechanisms of directional transport in neurons","volume":"6","author":"Hirokawa","year":"2005","journal-title":"Nat Rev Neurosci"},{"key":"2023110804130084900_ref30","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1093\/brain\/awx370","article-title":"Hot-spot KIF5A mutations cause familial ALS","volume":"141","author":"Brenner","year":"2018","journal-title":"Brain"},{"key":"2023110804130084900_ref31","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1136\/jnnp-2019-320483","article-title":"Whole-exome sequencing identified novel KIF5A mutations in Chinese patients with amyotrophic lateral sclerosis and Charcot-Marie-tooth type 2","volume":"91","author":"He","year":"2020","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2023110804130084900_ref32","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/j.neuron.2018.02.027","article-title":"Genome-wide analyses identify KIF5A as a novel ALS gene","volume":"97","author":"Nicolas","year":"2018","journal-title":"Neuron"},{"key":"2023110804130084900_ref33","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1212\/WNL.0000000000011064","article-title":"Identification of a pathogenic intronic KIF5A mutation in an ALS-FTD kindred","volume":"95","author":"Saez-Atienzar","year":"2020","journal-title":"Neurology"},{"key":"2023110804130084900_ref34","doi-asserted-by":"crossref","first-page":"229.e1","DOI":"10.1016\/j.neurobiolaging.2018.08.006","article-title":"Mutation analysis of KIF5A in Chinese amyotrophic lateral sclerosis patients","volume":"73","author":"Zhang","year":"2019","journal-title":"Neurobiol Aging"},{"key":"2023110804130084900_ref35","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1136\/jnnp-2018-318395","article-title":"Mutation screening of the KIF5A gene in Chinese patients with amyotrophic lateral sclerosis","volume":"90","author":"Gu","year":"2019","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2023110804130084900_ref36","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1080\/21678421.2022.2164204","article-title":"Expanding the spectrum of KIF5A mutations-case report of a large kindred with familial ALS and overlapping syndrome","volume":"24","author":"Dulski","year":"2023","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"2023110804130084900_ref37","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1111\/cge.13585","article-title":"Intrafamilial variable spastic paraplegia\/ataxia\/ALS phenotype linked to a novel KIF5A mutation","volume":"96","author":"Faruq","year":"2019","journal-title":"Clin Genet"},{"key":"2023110804130084900_ref38","doi-asserted-by":"crossref","first-page":"732","DOI":"10.3389\/fgene.2019.00732","article-title":"Comprehensive genetic analysis of a Hungarian amyotrophic lateral sclerosis cohort","volume":"10","author":"Tripolszki","year":"2019","journal-title":"Front Genet"},{"key":"2023110804130084900_ref39","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3390\/jcm8010017","article-title":"A novel mutation in the stalk domain of KIF5A causes a slowly progressive atypical motor syndrome","volume":"8","author":"Filosto","year":"2018","journal-title":"J Clin Med"},{"key":"2023110804130084900_ref40","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.3389\/fneur.2018.01078","article-title":"KIF5A and ALS2 variants in a family with hereditary spastic paraplegia and amyotrophic lateral sclerosis","volume":"9","author":"Simone","year":"2018","journal-title":"Front Neurol"},{"key":"2023110804130084900_ref41","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.jns.2016.03.001","article-title":"Late-onset spastic paraplegia type 10 (SPG10) family presenting with bulbar symptoms and fasciculations mimicking amyotrophic lateral sclerosis","volume":"364","author":"Kaji","year":"2016","journal-title":"J Neurol Sci"},{"key":"2023110804130084900_ref42","doi-asserted-by":"crossref","first-page":"110598","DOI":"10.1016\/j.celrep.2022.110598","article-title":"ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function","volume":"39","author":"Baron","year":"2022","journal-title":"Cell Rep"},{"key":"2023110804130084900_ref43","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1111\/gtc.12936","article-title":"An ALS-associated KIF5A mutant forms oligomers and aggregates and induces neuronal toxicity","volume":"27","author":"Nakano","year":"2022","journal-title":"Genes Cells"},{"key":"2023110804130084900_ref44","doi-asserted-by":"crossref","first-page":"e54234","DOI":"10.15252\/embr.202154234","article-title":"ALS-linked KIF5A \u0394Exon27 mutant causes neuronal toxicity through gain-of-function","volume":"23","author":"Pant","year":"2022","journal-title":"EMBO Rep"},{"key":"2023110804130084900_ref45","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/978-1-61779-767-5_3","article-title":"Minigenes to confirm exon skipping mutations","volume":"867","author":"Desviat","year":"2012","journal-title":"Methods Mol Biol"},{"key":"2023110804130084900_ref46","doi-asserted-by":"crossref","first-page":"e51","DOI":"10.1002\/cpcb.51","article-title":"Transcription factor-mediated differentiation of human iPSCs into neurons","volume":"79","author":"Fernandopulle","year":"2018","journal-title":"Curr Protoc Cell Biol"},{"key":"2023110804130084900_ref47","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1097\/00007890-196411000-00001","article-title":"Evaluation of the TRYPAN blue technique for determination of cell viability","volume":"2","author":"Tennant","year":"1964","journal-title":"Transplantation"},{"key":"2023110804130084900_ref48","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.neuron.2019.05.048","article-title":"Small-molecule modulation of TDP-43 recruitment to stress granules prevents persistent TDP-43 accumulation in ALS\/FTD","volume":"103","author":"Fang","year":"2019","journal-title":"Neuron"},{"key":"2023110804130084900_ref49","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.cell.2017.12.032","article-title":"Context-dependent and disease-specific diversity in protein interactions within stress granules","volume":"172","author":"Markmiller","year":"2018","journal-title":"Cell"},{"key":"2023110804130084900_ref50","doi-asserted-by":"crossref","first-page":"109685","DOI":"10.1016\/j.celrep.2021.109685","article-title":"Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress","volume":"36","author":"Markmiller","year":"2021","journal-title":"Cell Rep"},{"key":"2023110804130084900_ref51","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.neuron.2016.09.050","article-title":"Protein-RNA networks regulated by normal and ALS-associated mutant HNRNPA2B1 in the nervous system","volume":"92","author":"Martinez","year":"2016","journal-title":"Neuron"},{"key":"2023110804130084900_ref52","doi-asserted-by":"crossref","first-page":"106148","DOI":"10.1016\/j.nbd.2023.106148","article-title":"Impaired motor unit recovery and maintenance in a knock-in mouse model of ALS-associated Kif5a variant","volume":"182","author":"Rich","year":"2023","journal-title":"Neurobiol Dis"},{"key":"2023110804130084900_ref53","doi-asserted-by":"crossref","first-page":"2756","DOI":"10.1038\/s41467-021-22780-2","article-title":"Hotspot exons are common targets of splicing perturbations","volume":"12","author":"Glidden","year":"2021","journal-title":"Nat Commun"},{"key":"2023110804130084900_ref54","first-page":"893","article-title":"RNA-binding proteins: splicing factors and disease","volume":"5","author":"Fredericks","year":"2015","journal-title":"Biomol Ther"},{"key":"2023110804130084900_ref55","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/nrg3778","article-title":"Context-dependent control of alternative splicing by RNA-binding proteins","volume":"15","author":"Fu","year":"2014","journal-title":"Nat Rev Genet"},{"key":"2023110804130084900_ref56","first-page":"2675","article-title":"The missing puzzle piece: splicing mutations","volume":"6","author":"Lewandowska","year":"2013","journal-title":"Int J Clin Exp Pathol"},{"key":"2023110804130084900_ref57","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/nsmb0606-472","article-title":"Splicing fidelity revisited","volume":"13","author":"Query","year":"2006","journal-title":"Nat Struct Mol Biol"},{"key":"2023110804130084900_ref58","doi-asserted-by":"crossref","first-page":"3955","DOI":"10.1093\/nar\/gkl556","article-title":"Comprehensive splice-site analysis using comparative genomics","volume":"34","author":"Sheth","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"2023110804130084900_ref59","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/nrg.2016.46","article-title":"Lessons from non-canonical splicing","volume":"17","author":"Sibley","year":"2016","journal-title":"Nat Rev Genet"},{"key":"2023110804130084900_ref60","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1017\/S1355838299981682","article-title":"Genome-wide bioinformatic and molecular analysis of introns in Saccharomyces cerevisiae","volume":"5","author":"Spingola","year":"1999","journal-title":"RNA"},{"key":"2023110804130084900_ref61","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/nature14475","article-title":"Genome-wide identification of zero nucleotide recursive splicing in drosophila","volume":"521","author":"Duff","year":"2015","journal-title":"Nature"},{"key":"2023110804130084900_ref62","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1016\/j.cell.2014.11.035","article-title":"A highly conserved program of neuronal microexons is misregulated in autistic brains","volume":"159","author":"Irimia","year":"2014","journal-title":"Cell"},{"key":"2023110804130084900_ref63","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.molcel.2015.03.027","article-title":"Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed","volume":"58","author":"Rybak-Wolf","year":"2015","journal-title":"Mol Cell"},{"key":"2023110804130084900_ref64","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/nature14466","article-title":"Recursive splicing in long vertebrate genes","volume":"521","author":"Sibley","year":"2015","journal-title":"Nature"},{"key":"2023110804130084900_ref65","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1073\/pnas.1502849112","article-title":"Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators","volume":"112","author":"Yan","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023110804130084900_ref66","doi-asserted-by":"crossref","first-page":"20523","DOI":"10.1073\/pnas.1006869107","article-title":"Deficits in axonal transport precede ALS symptoms in vivo","volume":"107","author":"Bilsland","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023110804130084900_ref67","doi-asserted-by":"crossref","first-page":"594975","DOI":"10.3389\/fncel.2020.594975","article-title":"The neglected genes of ALS: cytoskeletal dynamics impact synaptic degeneration in ALS","volume":"14","author":"Castellanos-Montiel","year":"2020","journal-title":"Front Cell Neurosci"},{"key":"2023110804130084900_ref68","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.3390\/ijms13011225","article-title":"Disruption of axonal transport in motor neuron diseases","volume":"13","author":"Ikenaka","year":"2012","journal-title":"Int J Mol Sci"},{"key":"2023110804130084900_ref69","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0022-510X(00)00422-6","article-title":"Cytoskeletal abnormalities in amyotrophic lateral sclerosis: Beneficial or detrimental effects?","volume":"180","author":"Julien","year":"2000","journal-title":"J Neurol Sci"},{"key":"2023110804130084900_ref70","doi-asserted-by":"crossref","first-page":"12776","DOI":"10.1523\/JNEUROSCI.3463-09.2009","article-title":"Axonal transport defects in neurodegenerative diseases","volume":"29","author":"Morfini","year":"2009","journal-title":"J Neurosci"},{"key":"2023110804130084900_ref71","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/0022-510X(84)90199-0","article-title":"Neurofibrillary axonal swellings and amyotrophic lateral sclerosis","volume":"63","author":"Delisle","year":"1984","journal-title":"J Neurol Sci"},{"key":"2023110804130084900_ref72","first-page":"33","article-title":"Axonal transport in motor neuron pathology","volume":"19","author":"Griffin","year":"1976","journal-title":"UCLA Forum Med Sci"},{"key":"2023110804130084900_ref73","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1002\/(SICI)1097-0169(200004)45:4<249::AID-CM1>3.0.CO;2-M","article-title":"Phospho-dependent association of neurofilament proteins with kinesin in situ","volume":"45","author":"Yabe","year":"2000","journal-title":"Cell Motil Cytoskeleton"},{"key":"2023110804130084900_ref74","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/35040102","article-title":"Slow axonal transport: stop and go traffic in the axon","volume":"1","author":"Brown","year":"2000","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2023110804130084900_ref75","doi-asserted-by":"crossref","first-page":"3895","DOI":"10.1038\/s41467-022-31686-6","article-title":"Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure","volume":"13","author":"Gerasimavicius","year":"2022","journal-title":"Nat Commun"},{"key":"2023110804130084900_ref76","doi-asserted-by":"crossref","first-page":"e66273","DOI":"10.1371\/journal.pone.0066273","article-title":"Cancer missense mutations alter binding properties of proteins and their interaction networks","volume":"8","author":"Nishi","year":"2013","journal-title":"PLoS One"},{"key":"2023110804130084900_ref77","doi-asserted-by":"crossref","first-page":"3919","DOI":"10.1016\/j.jmb.2013.07.014","article-title":"Molecular mechanisms of disease-causing missense mutations","volume":"425","author":"Stefl","year":"2013","journal-title":"J Mol Biol"},{"key":"2023110804130084900_ref78","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1002\/prot.23065","article-title":"A missense mutation in CLIC2 associated with intellectual disability is predicted by in silico modeling to affect protein stability and dynamics","volume":"79","author":"Witham","year":"2011","journal-title":"Proteins"},{"key":"2023110804130084900_ref79","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.ajhg.2017.08.004","article-title":"Spatial clustering of de novo missense mutations identifies candidate neurodevelopmental disorder-associated genes","volume":"101","author":"Lelieveld","year":"2017","journal-title":"Am J Hum Genet"},{"key":"2023110804130084900_ref80","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.ajhg.2018.01.017","article-title":"Comprehensive analysis of constraint on the spatial distribution of missense variants in human protein structures","volume":"102","author":"Sivley","year":"2018","journal-title":"Am J Hum Genet"},{"key":"2023110804130084900_ref81","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/1476-4598-10-54","article-title":"The structural impact of cancer-associated missense mutations in oncogenes and tumor suppressors","volume":"10","author":"Stehr","year":"2011","journal-title":"Mol Cancer"},{"key":"2023110804130084900_ref82","doi-asserted-by":"crossref","first-page":"5995","DOI":"10.1093\/hmg\/ddv309","article-title":"Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns","volume":"24","author":"Turner","year":"2015","journal-title":"Hum Mol Genet"},{"key":"2023110804130084900_ref83","doi-asserted-by":"crossref","first-page":"36337","DOI":"10.1074\/jbc.M104236200","article-title":"Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9","volume":"276","author":"Buratti","year":"2001","journal-title":"J Biol Chem"},{"key":"2023110804130084900_ref84","doi-asserted-by":"crossref","first-page":"7871","DOI":"10.1073\/pnas.96.14.7871","article-title":"Single-nucleotide polymorphisms can cause different structural folds of mRNA","volume":"96","author":"Shen","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023110804130084900_ref85","doi-asserted-by":"crossref","first-page":"e73888","DOI":"10.7554\/eLife.73888","article-title":"Quantitative prediction of variant effects on alternative splicing in MAPT using endogenous pre-messenger RNA structure probing","volume":"11","author":"Kumar","year":"2022","journal-title":"elife"},{"key":"2023110804130084900_ref86","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.celrep.2013.09.043","article-title":"Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins","volume":"5","author":"Ciryam","year":"2013","journal-title":"Cell Rep"},{"key":"2023110804130084900_ref87","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.sbi.2017.01.004","article-title":"Exploring the relationships between protein sequence, structure and solubility","volume":"42","author":"Trainor","year":"2017","journal-title":"Curr Opin Struct Biol"},{"key":"2023110804130084900_ref88","doi-asserted-by":"crossref","first-page":"3345","DOI":"10.1016\/j.ymthe.2021.04.008","article-title":"Gene therapy for ALS: a review","volume":"29","author":"Amado","year":"2021","journal-title":"Mol Ther"},{"key":"2023110804130084900_ref89","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.nbd.2017.02.004","article-title":"Neurobiology of axonal transport defects in motor neuron diseases: Opportunities for translational research?","volume":"105","author":"De Vos","year":"2017","journal-title":"Neurobiol Dis"},{"key":"2023110804130084900_ref90","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1016\/j.clinph.2011.04.021","article-title":"Electrical impedance myography for monitoring motor neuron loss in the SOD1 G93A amyotrophic lateral sclerosis rat","volume":"122","author":"Wang","year":"2011","journal-title":"Clin Neurophysiol"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddad134\/51344541\/ddad134.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/22\/3166\/52808577\/ddad134.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/22\/3166\/52808577\/ddad134.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T04:13:53Z","timestamp":1699416833000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/32\/22\/3166\/7245776"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,18]]},"references-count":90,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,8,18]]},"published-print":{"date-parts":[[2023,11,3]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddad134","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,11,15]]},"published":{"date-parts":[[2023,8,18]]}}}