دورية أكاديمية
أعرض في EDS

Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling.

التفاصيل البيبلوغرافية
العنوان: Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling.
المؤلفون: Marom R; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.; Texas Children's Hospital, Houston, Texas, United States of America., Zhang B; Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, United States of America., Washington ME; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America., Song IW; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America., Burrage LC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.; Texas Children's Hospital, Houston, Texas, United States of America., Rossi VC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.; Texas Children's Hospital, Houston, Texas, United States of America., Berrier AS; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America., Lindsey A; Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, United States of America., Lesinski J; Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, United States of America., Nonet ML; Department of Neuroscience, Washington University School of Medicine, St Louis, Missouri, United States of America., Chen J; Department of Genetics, Washington University School of Medicine, St Louis, Missouri, United States of America., Baldridge D; Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, United States of America., Silverman GA; Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, United States of America., Sutton VR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.; Texas Children's Hospital, Houston, Texas, United States of America., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America., Tran AA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America., Hicks MJ; Texas Children's Hospital, Houston, Texas, United States of America.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, United States of America., Murdock DR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America., Dai H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America., Weis M; Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America., Jhangiani SN; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America., Muzny DM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America., Gibbs RA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America., Caswell R; Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom., Pottinger C; All Wales Medical Genomics Service, Wrexham Maelor Hospital, Wrexham, UK., Cilliers D; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom., Stals K; Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom., Eyre D; Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America., Krakow D; Human Genetics, Obstetrics & Gynecology, Orthopedic Surgery, University of California, Los Angeles, California, United States of America., Schedl T; Department of Genetics, Washington University School of Medicine, St Louis, Missouri, United States of America., Pak SC; Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, United States of America., Lee BH; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.; Texas Children's Hospital, Houston, Texas, United States of America.
مؤلفون مشاركون: Undiagnosed Diseases Network
المصدر: PLoS genetics [PLoS Genet] 2023 Nov 07; Vol. 19 (11), pp. e1011005. Date of Electronic Publication: 2023 Nov 07 (Print Publication: 2023).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE
أسماء مطبوعة: Original Publication: San Francisco, CA : Public Library of Science, c2005-
مواضيع طبية MeSH: Kinesins*/genetics , Kinesins*/metabolism , Osteogenesis Imperfecta*, Animals ; Humans ; Mice ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Carrier Proteins/genetics ; Down-Regulation ; NIH 3T3 Cells ; Proteomics ; Signal Transduction/genetics ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism
مستخلص: Background: Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, 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.
Methods: To understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, unc-116, 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.
Results: C. elegans heterozygous for the unc-116 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 unc-116 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.
Conclusion: We report dominant negative variants in the KIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for KIF5B in skeletal development.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Marom et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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معلومات مُعتمدة: R01 GM100756 United States GM NIGMS NIH HHS; U54 NS108251 United States NS NINDS NIH HHS; U01 HG007709 United States HG NHGRI NIH HHS; P30 DK056338 United States DK NIDDK NIH HHS; S10 OD030414 United States OD NIH HHS; U01 HG007703 United States HG NHGRI NIH HHS; U01 HG007942 United States HG NHGRI NIH HHS; P50 HD103555 United States HD NICHD NIH HHS; T32 GM007526 United States GM NIGMS NIH HHS; P40 OD010440 United States OD NIH HHS; P30 ES030285 United States ES NIEHS NIH HHS; P30 CA125123 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Carrier Proteins)
EC 3.6.4.4 (Kinesins)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
0 (KIF5B protein, human)
EC 3.6.1.- (Kif5b protein, mouse)
تواريخ الأحداث: Date Created: 20231107 Date Completed: 20231121 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC10656020
DOI: 10.1371/journal.pgen.1011005
PMID: 37934770
قاعدة البيانات: MEDLINE
الوصف
تدمد:1553-7404
DOI:10.1371/journal.pgen.1011005