ESPEYB21 14. The Year in Science and Medicine Bone (2 abstracts)
14.15. Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling
Ronit Marom , Bo Zhang , Megan E. Washington , I-Wen Song , Lindsay C. Burrage , Vittoria C. Rossi , Ava S. Berrier , Anika Lindsey , Jacob Lesinski , Michael L. Nonet , Jian Chen , Dustin Baldridge , Gary A. Silverman , V. Reid Sutton , Jill A. Rosenfeld , Alyssa A. Tran , M. John Hicks , David R. Murdock , Hongzheng Dai , MaryAnn Weis , Shalini N. Jhangiani , Donna M. Muzny , Richard A. Gibbs , Richard Caswell , Carrie Pottinger , Deirdre Cilliers , Karen Stals , Undiagnosed Diseases Network , David Eyre , Deborah Krakow , Tim Schedl , Stephen C. Pak & Brendan H. Lee
PLoS Genet. 2023 Nov 7;19(11):e1011005. doi: 10.1371/journal.pgen.1011005
Brief Summary:Heterozygous, de novo variants in KIF5B are identified in 4 individuals with osteogenesis imperfecta. Studies of these KIF5B variants in C. elegans and cell models reveal the disease-causing mechanism. KIF5B seems important for intracellular trafficking and mTOR signaling to maintain skeletal homeostasis.
Several years after the description of the last new osteogenesis imperfecta (OI)-related gene, the authors report on new dominant negative KIF5B gene variants in unrelated individuals with OI. KIF5B belongs to the kinesin superfamily proteins that play a key role in cellular function like cell cycle, endocytosis and ciliogenesis. Kinesin-1 heavy chains are encoded by KIFB genes. Pathogenic variants in KIF genes lead to multisystemic disorders known as ‘kinesinopathies’. They have been associated with variable human phenotypes, including neurodevelopmental disorders and skeletal dysplasias. Previously, KIFB5 variants were reported in individuals with and without skeletal dysplasias.
The authors describe novel variants of the KIFB5 gene located in the specific kinesin motor domain of the protein; all manifesting with OI, a new phenotype for kinesinopathies.
Mechanistic studies in bone tissue and fibroblasts of these KIFB5 variant patients revealed a downstream inhibition on mTOR signaling pathway likely responsible for the bone phenotype. By showing positive rescue through reestablishing mTOR signaling with the essential amino acid leucine (a known stimulator of mTOR), the authors confirm the critical role of mTOR in KIFB5 related OI and propose possible targets for future therapeutic approaches.
Volume 21
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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