{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T18:29:01Z","timestamp":1791052141820,"version":"4.1.0"},"reference-count":57,"publisher":"American Society for Clinical Investigation","issue":"11","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":41,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH NINDS","award":["1K08NS131581"],"award-info":[{"award-number":["1K08NS131581"]}]},{"name":"NIH","award":["R37 NS096241"],"award-info":[{"award-number":["R37 NS096241"]}]},{"name":"NIH NINDS","award":["R35 NS122257"],"award-info":[{"award-number":["R35 NS122257"]}]},{"name":"Aligning Science Across Parkinson\u2019s","award":["GP2"],"award-info":[{"award-number":["GP2"]}]},{"DOI":"10.13039\/100013301","name":"Parkinson\u2019s Foundation","doi-asserted-by":"crossref","award":["PF-SPE-874858"],"award-info":[{"award-number":["PF-SPE-874858"]}],"id":[{"id":"10.13039\/100013301","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["HD001607"],"award-info":[{"award-number":["HD001607"]}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["OGB-177940"],"award-info":[{"award-number":["OGB-177940"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,1]]},"abstract":"<jats:p>\n                    <jats:italic>BORCS5<\/jats:italic>\n                    encodes a subunit of the BLOC-One-Related Complex (BORC), which is known to promote anterograde movement and fusion of lysosomes. We identified 16 individuals from 9 families with bi-allelic\n                    <jats:italic>BORCS5<\/jats:italic>\n                    variants, revealing a spectrum of neurodevelopmental and neurodegenerative phenotypes. Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, and progressive global cerebral atrophy, consistent with neurodegeneration.\n                    <jats:italic>Borcs5<\/jats:italic>\n                    KO in zebrafish resulted in microcephaly, motor deficits, and increased seizure susceptibility, mirroring the patients\u2019 clinical presentation. At the cellular level, only BORCS5 PTVs, but not missense variants, led to perinuclear lysosomal clustering and impaired lysosomal axonal trafficking in induced pluripotent stem cell\u2013derived forebrain neurons. However, PTVs and missense variants were associated with reduced lysosomal proteolysis and activity of lysosomal hydrolases glucocerebrosidase and cathepsin B, indicating lysosomal dysfunction. Our study reveals a role for BORCS5 in modulation of lysosomal function, in addition to its known role in lysosome movement and fusion, possibly underlying the diverse clinical manifestations in individuals with BORCS5-related disorders.\n                  <\/jats:p>","DOI":"10.1172\/jci195336","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T16:00:31Z","timestamp":1776787231000},"source":"Crossref","is-referenced-by-count":2,"title":["Pathogenic variants in BORCS5 cause a spectrum of neurodevelopmental and neurodegenerative disorders with lysosomal dysfunction"],"prefix":"10.1172","volume":"136","author":[{"given":"Niccol\u00f2 E.","family":"Mencacci","sequence":"first","affiliation":[{"name":"Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Minakaki","sequence":"additional","affiliation":[{"name":"Davee 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