{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T04:23:52Z","timestamp":1793075032829,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011611","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000}}],"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T00:00:00Z","timestamp":1755475200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Grants Council-Collaborative Research Fund","award":["CRF-C2103-20GF"],"award-info":[{"award-number":["CRF-C2103-20GF"]}]},{"DOI":"10.13039\/501100001747","name":"Hong Kong Baptist University","doi-asserted-by":"publisher","award":["Seed Fund"],"award-info":[{"award-number":["Seed Fund"]}],"id":[{"id":"10.13039\/501100001747","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Medical Research Grant Council, Singapore-Young Individual Research Grant","award":["NMRC\/OFYIRG\/0079\/2018"],"award-info":[{"award-number":["NMRC\/OFYIRG\/0079\/2018"]}]},{"name":"UKRI Medical Research Council"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    The primary cilium is a signal transduction organelle whose dysfunction clinically causes ciliopathies in humans. RAB23 is a small GTPase known to regulate the Hedgehog signalling pathway and ciliary trafficking. Mutations of\n                    <jats:italic>RAB23<\/jats:italic>\n                    in humans lead to Carpenter syndrome (CS), an autosomal recessive disorder clinically characterized by craniosynostosis, polysyndactyly, skeletal defects, obesity, and intellectual disability. Although the clinical features of CS bear some resemblance to those of ciliopathies, the exact relationship between the pathological manifestations of CS and the ciliary function of\n                    <jats:italic>RAB23<\/jats:italic>\n                    remains ambiguous. Besides, the\n                    <jats:italic>\n                      <jats:italic>in vivo<\/jats:italic>\n                    <\/jats:italic>\n                    ciliary functions of\n                    <jats:italic>RAB23<\/jats:italic>\n                    remain poorly characterised. Here, we demonstrate\n                    <jats:italic>\n                      <jats:italic>in vivo<\/jats:italic>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      <jats:italic>in vitro Rab23<\/jats:italic>\n                    <\/jats:italic>\n                    loss-of-function mutants modelling CS, including\n                    <jats:italic>\n                      <jats:italic>Rab23<\/jats:italic>\n                    <\/jats:italic>\n                    conditional knockout (CKO) mouse mutants, CS patient-derived induced pluripotent stem cells (iPSCs), and zebrafish morphants. The\n                    <jats:italic>\n                      <jats:italic>Rab23<\/jats:italic>\n                    <\/jats:italic>\n                    -CKO mutants exhibit multiple developmental and phenotypical traits recapitulating the clinical features of human ciliopathies and CS, indicating a causal link between the loss of\n                    <jats:italic>\n                      <jats:italic>Rab23<\/jats:italic>\n                    <\/jats:italic>\n                    and ciliopathy. In line with the ciliopathy-like phenotypes, all three different vertebrate mutant models consistently show a perturbation of primary cilia formation, intriguingly, in a context-dependent manner.\n                    <jats:italic>\n                      <jats:italic>Rab23<\/jats:italic>\n                    <\/jats:italic>\n                    -CKO mutants reveal cell-type specific ciliary abnormalities in chondrocytes, mouse embryonic fibroblasts, neural progenitor cells and neocortical neurons, but not in epithelial cells, cerebellar granule cells and hippocampus neurons. A profound reduction in ciliation frequency was observed specifically in neurons differentiated from CS patient iPSCs, whereas the patients\u2019 fibroblasts, iPSCs and neural progenitor cells maintained normal ciliation percentages but shortened cilia length. Furthermore,\n                    <jats:italic>\n                      <jats:italic>Rab23<\/jats:italic>\n                    <\/jats:italic>\n                    -KO neural progenitor cells show perturbed ciliation and desensitized to primary cilium-dependent activation of the Hedgehog signaling pathway. Collectively, these findings indicate that the absence of\n                    <jats:italic>RAB23<\/jats:italic>\n                    causes dysfunctional primary cilia in a cell-type distinctive manner, which underlies the pathological manifestations of CS. Our findings present the first\n                    <jats:italic>\n                      <jats:italic>in vivo<\/jats:italic>\n                    <\/jats:italic>\n                    evidence validating the unique context-specific function of\n                    <jats:italic>RAB23<\/jats:italic>\n                    in the primary cilium. Through the use of patient-derived iPSCs differentiated cells, we present direct evidence of primary cilia anomalies in CS, thereby confirming CS as a ciliopathy disorder.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011611","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T17:56:16Z","timestamp":1755539776000},"page":"e1011611","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome"],"prefix":"10.1371","volume":"21","author":[{"given":"Wan Ying","family":"Leong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2470-5747","authenticated-orcid":true,"given":"Wai Lam","family":"Tung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2972-5481","authenticated-orcid":true,"given":"Andrew O. 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