WoS İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/394
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Article Bi-Allelic Variants in OLA1 Cause a Neurodevelopmental Disorder with Joint Hypermobility(Cell Press, 2026-04) Cevik, Sebiha; Alzahrani, Fatema; Sezer, Abdullah; AlAbdi, Lama; Demir, Zanyar; Abdullah, Nor Linda; Alkuraya, Fowzan S.Cytoskeletal organization, cell adhesion, and cell motility are key to neuronal development and functional synapses. Obg-like ATPase 1 (OLA1) regulates cell-matrix adhesion by modulating focal adhesion kinase (FAK) levels, therefore regulating cytoskeletal dynamics and cell motility. To date, however, no Mendelian phenotypes in humans have been linked to OLA1. We identified fourteen individuals from nine families in whom hypermobility-neurodevelopmental disorder with distinct facies is linked to bi-allelic deleterious variants in OLA1. The hypermobility phenotype evoked a diagnosis of Ehlers-Danlos syndrome (EDS) in some affected individuals. The loss-of-function nature of these variants is confirmed in proband-derived fibroblasts, recapitulating the impaired migration and proliferation phenotype previously described in OLA1-deficient cells. To explore the pathogenesis of abnormal neurodevelopment in our probands, we investigated neurons derived from proband fibroblasts and identified impaired adhesion and cytoskeletal control. Modeling ola-1 deficiency in C. elegans revealed reduced neurite numbers compared to the wild type. Additionally, transcriptomic analysis of the ola-1-deficient worms suggested that dysregulation of key signaling pathways results in suppression of microtubule dynamics and axon regrowth, ultimately crippling the regenerative competence of mutant animals compared to wild-type controls. Our results support an autosomal-recessive OLA1-related hypermobility-neurodevelopmental disorder and suggest that dysregulation of key signaling pathways results in the suppression of microtubule dynamics as a potential underlying mechanism.