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.Conference Object The Understanding the Role of Mitochondria in Cilia and Ciliopathy(Springer Nature, 2025) Cevik, Sebiha; Guzel, Fatma; Yilmaz, Gul Hanim; Oner, Sadik; Sezer, Abdullah; Kaplan, Oktay I.Conference Object PATL1: A Novel Candidate Gene for Neurodevelopmental Disorders with Motor Impairment(Springer Nature, 2025) Alders, Marielle; Maas, Saskia; Sezer, Abdullah; Percin, Ferda Emriye; Kayhan, Gulsum; Kaplan, Oktay Ismail; Yenisert, FerhanConference Object Understanding the Role of FAM120A Gene in a Neurodevelopmental Disorder(Springernature, 2024) Sezer, Abdullah; Pucak, Damla; Cevik, Sebiha; Kaplan, Oktay I.Article Citation - WoS: 1Citation - Scopus: 1A Homozygous Frameshift Variant in the CILK1 Gene Causes Cranioectodermal Dysplasia(Springernature, 2025-07-04) Sezer, Abdullah; Oner, Sukru S.; Saat, Hanife; Turan, Merve G.; Gungor, Tulin; Cevik, Sebiha; Kaplan, Oktay I.Cranioectodermal dysplasia (CED) is a ciliopathy characterized by skeletal and ectodermal abnormalities, renal failure, and liver fibrosis. Pathogenic variants in genes that encode the intraflagellar transport (IFT) complex components, particularly IFT-A, are responsible for approximately two-thirds of the CED cases. However, the cause of the remaining cases remains unknown. Ciliogenesis-associated kinase 1 (CILK1) is a highly conserved ciliary serine/threonine kinase with an N-terminal catalytic domain responsible for kinase activity and a C-terminal non-catalytic domain that interacts with the IFT-B complex. Biallelic variants in the catalytic domain are associated with lethal skeletal dysplasia, endocrine cerebroosteodysplasia, and short-rib polydactyly syndrome. No human disease has been linked to biallelic variants in the non-catalytic domain. We present a homozygous frameshift variant in the CILK1 gene that affects the distal part of the non-catalytic domain, causing CED in five patients from two pedigrees. All the patients survived into childhood and had disproportionately short stature, skeletal abnormalities, ectodermal dysplasia, renal issues, and liver complications. Functional data from patient-derived cells and the C. elegans model indicate that the variant reduces cilia number, increases cilia length, and disrupts the localization of IFT components. In contrast, the ciliary localization of CILK1 bearing the variant itself remains unaffected. Notably, we rescued the majority of these abnormalities by reintroducing CILK1 into patient-derived cells. Finally, our study describes CILK1 as a novel causal gene and the first non-IFT protein-encoding gene in the etiology of CED, thus expanding the known genotypic, mechanistic, and phenotypic spectrum of CED.