WoS İndeksli Yayınlar Koleksiyonu

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/394

Browse

Filters

20252

Settings

Publication Index: search.filters.publicationIndex.PubMedPublisher: search.filters.publisher.Springernature

Search Results

Now showing 1 - 2 of 2
  • Article
    Citation - WoS: 1
    Citation - Scopus: 1
    A 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.
  • Article
    Citation - WoS: 1
    Citation - Scopus: 1
    A Comprehensive MicroRNA-seq Transcriptomic Analysis of Tay-Sachs Disease Mice Revealed Distinct miRNA Profiles in Neuroglial Cells
    (Springernature, 2025-08-09) Kaya, Beyza; Orhan, Mehmet Emin; Yanbul, Selman; Demirci, Muserref Duygu Sacar; Demir, Secil Akyildiz; Seyrantepe, Volkan
    Tay-Sachs disease (TSD) is a rare lysosomal storage disorder marked by the progressive buildup of GM2 in the central nervous system (CNS). This condition arises from mutations in the HEXA gene, which encodes the alpha subunit of the enzyme beta-hexosaminidase A. A newly developed mouse model for early-onset TSD (Hexa-/-Neu3-/-) exhibited signs of neurodegeneration and neuroinflammation, evidenced by elevated levels of pro-inflammatory cytokines and chemokines, as well as significant astrogliosis and microgliosis. Identifying disease-specific MicroRNAs (miRNAs) may aid the development of targeted therapies. Although previous small-scale studies have investigated miRNA expression in some regions of GM2 gangliosidosis mouse models, thorough profiling of miRNAs in this innovative TSD model remains to be done. In this study, we employed next-generation sequencing to analyze the complete miRNA profile of neuroglial cells from Hexa-/-Neu3-/- mice. By comparing KEGG and Reactome pathways associated with neurodegeneration, neuroinflammation, and sphingolipid metabolism in Hexa-/-Neu3-/- neuroglial cells, we discovered new MicroRNAs and their targets related to the pathophysiology of GM2 gangliosidosis. For the first time, our findings showed that miR-708-5p, miR-672-5p, miR-204-5p, miR-335-5p, and miR-296-3p were upregulated, while miR-10 b-5p, miR-615-3p, miR-196a-5p, miR-214-5p, and miR-199a-5p were downregulated in Hexa-/-Neu3-/- neuroglial cells in comparison to age-matched wild-type (WT). These specific changes in miRNA expression deepen our understanding of the disease's neuropathological characteristics in Hexa-/-Neu3-/- mice. Our study suggests that miRNA-based therapeutic strategies may improve clinical outcomes for TSD patients.