{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:46:03Z","timestamp":1768567563222,"version":"3.49.0"},"posted":{"date-parts":[[2025,5,7]]},"group-title":"Neurology","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>BORCS5<\/jats:italic>\n                  encodes a subunit of the BLOC-one-related complex (BORC), which is known to mediate the kinesin-dependent anterograde movement of lysosomes. Using whole-exome sequencing, we identified 12 cases from seven families carrying bi-allelic\n                  <jats:italic>BORCS5<\/jats:italic>\n                  variants, including four loss-of-function and two missense variants. Carriers of homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration.\n                  <jats:italic>Borcs5<\/jats:italic>\n                  knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients\u2019 clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction. Our study reveals a novel role for BORCS5 in the regulation of lysosomal function, in addition to its known role in the anterograde movement of lysosomes, possibly underlying the diverse clinical manifestations in individuals with BORCS5-related disorders.\n                <\/jats:p>","DOI":"10.1101\/2025.04.30.25326597","type":"posted-content","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T16:10:19Z","timestamp":1746634219000},"source":"Crossref","is-referenced-by-count":2,"title":["Pathogenic variants in\n                  <i>BORCS5<\/i>\n                  Cause a Spectrum of Neurodevelopmental and Neurodegenerative Disorders with Lysosomal Dysfunction"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3383-9665","authenticated-orcid":false,"given":"Niccol\u00f2 E.","family":"Mencacci","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1090-4241","authenticated-orcid":false,"given":"Georgia","family":"Minakaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6763-1542","authenticated-orcid":false,"given":"Reza","family":"Maroofian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8179-6869","authenticated-orcid":false,"given":"Raffaella De","family":"Pace","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5822-3088","authenticated-orcid":false,"given":"Adeline","family":"Paimboeuf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3309-8118","authenticated-orcid":false,"given":"Patrick","family":"Shannon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1944-7294","authenticated-orcid":false,"given":"David","family":"Chitayat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4706-6245","authenticated-orcid":false,"given":"Francesca","family":"Magrinelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4683-170X","authenticated-orcid":false,"given":"Wesley J.","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7959-7529","authenticated-orcid":false,"given":"Diptaman","family":"Chatterjee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7572-9128","authenticated-orcid":false,"given":"Sara H.","family":"Eldessouky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0915-5028","authenticated-orcid":false,"given":"Julia","family":"Baptista","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5585-2276","authenticated-orcid":false,"given":"Tamas","family":"Marton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7459-0176","authenticated-orcid":false,"given":"Julie","family":"Vogt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6320-2641","authenticated-orcid":false,"given":"Juan Dario","family":"Ortigoza-Escobar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0898-7332","authenticated-orcid":false,"given":"Loreto","family":"Martorell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6726-1721","authenticated-orcid":false,"given":"Marta","family":"G\u00f3mez-Chiari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6994-1640","authenticated-orcid":false,"given":"Ingrid M","family":"Wentzensen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6480-1892","authenticated-orcid":false,"given":"Erik-Jan","family":"Kamsteeg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7840-0002","authenticated-orcid":false,"given":"Maha S.","family":"Zaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6013-4819","authenticated-orcid":false,"given":"Annarita","family":"Scardamaglia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5567-8300","authenticated-orcid":false,"given":"Giovanni","family":"Zifarelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7173-2044","authenticated-orcid":false,"given":"Zuhair Nasser","family":"Al-Hassnan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1075-5952","authenticated-orcid":false,"given":"Elka","family":"Miller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6352-4846","authenticated-orcid":false,"given":"Shiri","family":"Shinar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8215-3743","authenticated-orcid":false,"given":"Lova S.","family":"Matsa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5273-7296","authenticated-orcid":false,"given":"Sri Hari","family":"Chandan Appikonda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4173-2166","authenticated-orcid":false,"given":"Michael","family":"Schwake","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4730-5322","authenticated-orcid":false,"given":"Mariasavina","family":"Severino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2866-7777","authenticated-orcid":false,"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2782-3547","authenticated-orcid":false,"given":"Shunmoogum A.","family":"Patten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5673-6370","authenticated-orcid":false,"given":"Juan S.","family":"Bonifacino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8185-286X","authenticated-orcid":false,"given":"Kailash P.","family":"Bhatia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4716-1886","authenticated-orcid":false,"given":"Dimitri","family":"Krainc","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025050904401126000_2025.04.30.25326597v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27631"},{"key":"2025050904401126000_2025.04.30.25326597v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx285"},{"key":"2025050904401126000_2025.04.30.25326597v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25879"},{"key":"2025050904401126000_2025.04.30.25326597v1.4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/mds.30037","article-title":"Emerging Molecular-Genetic Families in Dystonia: Endosome-Autophagosome-Lysosome and Integrated Stress Response Pathways","volume":"40","year":"2025","journal-title":"Mov Disord"},{"key":"2025050904401126000_2025.04.30.25326597v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0185-4"},{"key":"2025050904401126000_2025.04.30.25326597v1.6","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202012836"},{"key":"2025050904401126000_2025.04.30.25326597v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.09.001"},{"key":"2025050904401126000_2025.04.30.25326597v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.02.011"},{"key":"2025050904401126000_2025.04.30.25326597v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELREP.2016.10.062"},{"key":"2025050904401126000_2025.04.30.25326597v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.10.007"},{"key":"2025050904401126000_2025.04.30.25326597v1.11","doi-asserted-by":"crossref","unstructured":"De Pace, R. et al. Synaptic Vesicle Precursors and Lysosomes Are Transported by Different Mechanisms in the Axon of Mammalian Neurons. Cell Rep 31, 107775 (2020).","DOI":"10.1016\/j.celrep.2020.107775"},{"key":"2025050904401126000_2025.04.30.25326597v1.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1616363114"},{"key":"2025050904401126000_2025.04.30.25326597v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.06.118"},{"key":"2025050904401126000_2025.04.30.25326597v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-024-01619-1"},{"key":"2025050904401126000_2025.04.30.25326597v1.15","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2017.1343768"},{"key":"2025050904401126000_2025.04.30.25326597v1.16","doi-asserted-by":"crossref","unstructured":"Shelke, G.V. , Williamson, C.D. , Jarnik, M. & Bonifacino, J.S . Inhibition of endolysosome fusion increases exosome secretion. J Cell Biol 222(2023).","DOI":"10.1083\/jcb.202209084"},{"key":"2025050904401126000_2025.04.30.25326597v1.17","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad427"},{"key":"2025050904401126000_2025.04.30.25326597v1.18","doi-asserted-by":"crossref","unstructured":"Charng, W.L. et al. Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate. BMC Med Genomics 9, 42 (2016).","DOI":"10.1186\/s12920-016-0208-3"},{"key":"2025050904401126000_2025.04.30.25326597v1.19","doi-asserted-by":"crossref","unstructured":"Abdel-Hamid, M.S. et al. Biallelic variants in GTF3C3 encoding a subunit of the TFIIIC2 complex are associated with neurodevelopmental phenotypes in humans and zebrafish. Brain Commun 7, fcaf055 (2025).","DOI":"10.1093\/braincomms\/fcaf055"},{"key":"2025050904401126000_2025.04.30.25326597v1.20","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.11.1.255"},{"key":"2025050904401126000_2025.04.30.25326597v1.21","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2017.1395992"},{"key":"2025050904401126000_2025.04.30.25326597v1.22","doi-asserted-by":"crossref","unstructured":"Miranda, A.M. et al. Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures. Nat Commun 9, 291 (2018).","DOI":"10.1038\/s41467-017-02533-w"},{"key":"2025050904401126000_2025.04.30.25326597v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-021-00693-y"},{"key":"2025050904401126000_2025.04.30.25326597v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.05.029"},{"key":"2025050904401126000_2025.04.30.25326597v1.25","doi-asserted-by":"crossref","unstructured":"Duquesne, S. , Nassogne, M.C. , Clapuyt, P. , Stouffs, K. & Sznajer, Y . Phenotype description in KIF5C gene hot-spot mutations responsible for malformations of cortical development (MCD). Eur J Med Genet 63, 103991 (2020).","DOI":"10.1016\/j.ejmg.2020.103991"},{"key":"2025050904401126000_2025.04.30.25326597v1.26","doi-asserted-by":"crossref","unstructured":"Poirier, K. et al. Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nat Genet 45, 639-47 (2013).","DOI":"10.1038\/ng.2613"},{"key":"2025050904401126000_2025.04.30.25326597v1.27","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12714"},{"key":"2025050904401126000_2025.04.30.25326597v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.4"},{"key":"2025050904401126000_2025.04.30.25326597v1.29","doi-asserted-by":"crossref","unstructured":"Saito, R. et al. A neuropathological cell model derived from Niemann-Pick disease type C patient-specific iPSCs shows disruption of the p62\/SQSTM1-KEAP1-NRF2 Axis and impaired formation of neuronal networks. Mol Genet Metab Rep 28, 100784 (2021).","DOI":"10.1016\/j.ymgmr.2021.100784"},{"key":"2025050904401126000_2025.04.30.25326597v1.30","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27119"},{"key":"2025050904401126000_2025.04.30.25326597v1.31","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1739-1"},{"key":"2025050904401126000_2025.04.30.25326597v1.32","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac047"},{"key":"2025050904401126000_2025.04.30.25326597v1.33","doi-asserted-by":"crossref","unstructured":"Arrant, A.E. et al. Impaired \u03b2-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations. Acta Neuropathol Commun 7, 218 (2019).","DOI":"10.1186\/s40478-019-0872-6"},{"key":"2025050904401126000_2025.04.30.25326597v1.34","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz229"},{"key":"2025050904401126000_2025.04.30.25326597v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30320-5"},{"key":"2025050904401126000_2025.04.30.25326597v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.06.001"},{"key":"2025050904401126000_2025.04.30.25326597v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70190-4"},{"key":"2025050904401126000_2025.04.30.25326597v1.38","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz350"},{"key":"2025050904401126000_2025.04.30.25326597v1.39","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28807"},{"key":"2025050904401126000_2025.04.30.25326597v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/ng1826"},{"key":"2025050904401126000_2025.04.30.25326597v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2010.05.009"},{"key":"2025050904401126000_2025.04.30.25326597v1.42","doi-asserted-by":"crossref","unstructured":"Riku, Y. et al. Extensive aggregation of \u03b1-synuclein and tau in juvenile-onset neuroaxonal dystrophy: an autopsied individual with a novel mutation in the PLA2G6 gene-splicing site. Acta Neuropathol Commun 1, 12 (2013).","DOI":"10.1186\/2051-5960-1-12"},{"key":"2025050904401126000_2025.04.30.25326597v1.43","doi-asserted-by":"crossref","unstructured":"Monfrini, E. et al. A Novel Homozygous VPS11 Variant May Cause Generalized Dystonia. Ann Neurol (2021).","DOI":"10.1002\/ana.26021"},{"key":"2025050904401126000_2025.04.30.25326597v1.44","doi-asserted-by":"crossref","first-page":"2610","DOI":"10.1093\/brain\/awab161","article-title":"HOPS-associated neurological disorders (HOPSANDs): linking endolysosomal dysfunction to the pathogenesis of dystonia","volume":"144","year":"2021","journal-title":"Brain"},{"key":"2025050904401126000_2025.04.30.25326597v1.45","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa459"},{"key":"2025050904401126000_2025.04.30.25326597v1.46","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202013258"},{"key":"2025050904401126000_2025.04.30.25326597v1.47","doi-asserted-by":"crossref","unstructured":"Y\u0131ld\u0131z, Y. et al. Homozygous missense VPS16 variant is associated with a novel disease, resembling mucopolysaccharidosis-plus syndrome in two siblings. Clin Genet (2021).","DOI":"10.1111\/cge.14002"},{"key":"2025050904401126000_2025.04.30.25326597v1.48","doi-asserted-by":"crossref","unstructured":"Le Fevre, A. et al. Compound heterozygous Pkd1l1 variants in a family with two fetuses affected by heterotaxy and complex Chd. Eur J Med Genet 63, 103657 (2020).","DOI":"10.1016\/j.ejmg.2019.04.014"},{"key":"2025050904401126000_2025.04.30.25326597v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.148"},{"key":"2025050904401126000_2025.04.30.25326597v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.02.015"},{"key":"2025050904401126000_2025.04.30.25326597v1.51","first-page":"e3703","article-title":"Measuring Intracellular Vesicle Density and Dispersion Using Fluorescence Microscopy and ImageJ\/FIJI","volume":"10","year":"2020","journal-title":"Bio Protoc"},{"key":"2025050904401126000_2025.04.30.25326597v1.52","doi-asserted-by":"publisher","DOI":"10.4161\/auto.1.1.1270"},{"key":"2025050904401126000_2025.04.30.25326597v1.53","first-page":"e3572","article-title":"Flow Cytometry Measurement of Glucocerebrosidase Activity in Human Monocytes","volume":"10","year":"2020","journal-title":"Bio-protocol"},{"key":"2025050904401126000_2025.04.30.25326597v1.54","doi-asserted-by":"crossref","unstructured":"Haeussler, M. et al. Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR. Genome Biol 17, 148 (2016).","DOI":"10.1186\/s13059-016-1012-2"},{"key":"2025050904401126000_2025.04.30.25326597v1.55","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1002030302"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.04.30.25326597","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:34:59Z","timestamp":1768509299000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.04.30.25326597"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,7]]},"references-count":55,"URL":"https:\/\/doi.org\/10.1101\/2025.04.30.25326597","relation":{},"subject":[],"published":{"date-parts":[[2025,5,7]]},"subtype":"preprint"}}