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Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified<jats:italic>de novo<\/jats:italic>, heterozygous variants in<jats:italic>KIF5B<\/jats:italic>, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>To understand the<jats:italic>in vivo<\/jats:italic>genetic mechanism of<jats:italic>KIF5B<\/jats:italic>variants, we modeled the p.Thr87Ile variant that was found in two patients in the<jats:italic>C<\/jats:italic>.<jats:italic>elegans<\/jats:italic>ortholog,<jats:italic>unc-116<\/jats:italic>, at the corresponding position (Thr90Ile) by CRISPR\/Cas9 editing and performed functional analysis. Next, we studied the cellular and molecular consequences of the recurrent p.Thr87Ile variant by microscopy, RNA and protein analysis in NIH3T3 cells, primary human fibroblasts and bone biopsy.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p><jats:italic>C<\/jats:italic>.<jats:italic>elegans<\/jats:italic>heterozygous for the<jats:italic>unc-116<\/jats:italic>Thr90Ile variant displayed abnormal body length and motility phenotypes that were suppressed by additional copies of the wild type allele, consistent with a dominant negative mechanism. Time-lapse imaging of GFP-tagged mitochondria showed defective mitochondria transport in<jats:italic>unc-116<\/jats:italic>Thr90Ile neurons providing strong evidence for disrupted kinesin motor function. Microscopy studies in human cells showed dilated endoplasmic reticulum, multiple intracellular vacuoles, and abnormal distribution of the Golgi complex, supporting an intracellular trafficking defect. RNA sequencing, proteomic analysis, and bone immunohistochemistry demonstrated down regulation of the mTOR signaling pathway that was partially rescued with leucine supplementation in patient cells.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Conclusion<\/jats:title><jats:p>We report dominant negative variants in the<jats:italic>KIF5B<\/jats:italic>kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for<jats:italic>KIF5B<\/jats:italic>in skeletal development.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pgen.1011005","type":"journal-article","created":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T18:31:50Z","timestamp":1699381910000},"page":"e1011005","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3524-661X","authenticated-orcid":true,"given":"Ronit","family":"Marom","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6198-7908","authenticated-orcid":true,"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9883-2408","authenticated-orcid":true,"given":"Megan E.","family":"Washington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1579-4328","authenticated-orcid":true,"given":"I-Wen","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5108-8861","authenticated-orcid":true,"given":"Lindsay C.","family":"Burrage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoria C.","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ava S.","family":"Berrier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4236-9223","authenticated-orcid":true,"given":"Anika","family":"Lindsey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Lesinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"Nonet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6027-6020","authenticated-orcid":true,"given":"Dustin","family":"Baldridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2686-2843","authenticated-orcid":true,"given":"Gary A.","family":"Silverman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V. 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