دورية أكاديمية
أعرض في EDS

A rare human CEP290 variant disrupts the molecular integrity of the primary cilium and impairs Sonic Hedgehog machinery.

التفاصيل البيبلوغرافية
العنوان: A rare human CEP290 variant disrupts the molecular integrity of the primary cilium and impairs Sonic Hedgehog machinery.
المؤلفون: Kilander MBC; Program in Neuroscience, Hussman Institute for Autism, Baltimore, MD, 21201, USA., Wang CH; Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei, 112, Taiwan., Chang CH; Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei, 112, Taiwan.; Taiwan International Graduate Program (TIGP) in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan., Nestor JE; Program in Neuroscience, Hussman Institute for Autism, Baltimore, MD, 21201, USA., Herold K; Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA., Tsai JW; Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei, 112, Taiwan.; Brain Research Center (BRC), and Biophotonics and Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei, 112, Taiwan., Nestor MW; Program in Neuroscience, Hussman Institute for Autism, Baltimore, MD, 21201, USA., Lin YC; Program in Neuroscience, Hussman Institute for Autism, Baltimore, MD, 21201, USA. yclin@hussmanautism.org.
المصدر: Scientific reports [Sci Rep] 2018 Nov 26; Vol. 8 (1), pp. 17335. Date of Electronic Publication: 2018 Nov 26.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: Mutation, Missense*, Antigens, Neoplasm/*genetics , Cell Cycle Proteins/*genetics , Cilia/*metabolism , Cytoskeletal Proteins/*genetics , Hedgehog Proteins/*metabolism , Induced Pluripotent Stem Cells/*metabolism, Animals ; Antigens, Neoplasm/metabolism ; Autistic Disorder/genetics ; Cell Cycle Proteins/metabolism ; Cell Proliferation ; Cilia/pathology ; Cytoskeletal Proteins/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; NIH 3T3 Cells ; Patched-1 Receptor/metabolism ; Signal Transduction/genetics ; Smoothened Receptor/metabolism
مستخلص: The primary cilium is a microtubule-enriched cell-communication organelle that participates in mechanisms controlling tissue development and maintenance, including cerebellar architecture. Centrosomal protein of 290 kDa (CEP290) is a protein important for centrosomal function and ciliogenesis. Mutations in CEP290 have been linked to a group of multi-organ disorders - termed ciliopathies. The neurophysiological deficits observed in ciliopathies are sometimes associated with the progression of autistic traits. Here, the cellular function of two rare variants of CEP290 identified from recent exome sequencing of autistic individuals are investigated. Cells expressing Cep290 carrying the missense mutation R1747Q in mouse exhibited a defective Sonic hedgehog (Shh) signalling response, mislocalisation of the Shh receptor Smoothened (Smo), and dysregulation of ciliary protein mobility, which ultimately disrupted the proliferation of cerebellar granule progenitors (CGPs). This data was furthermore corroborated in an autism patient-derived iPSC line harbouring the R1746Q rare CEP290 variant. Evidence from this study suggests that the R1746Q mutation interferes with the function of CEP290 to maintain the ciliary diffusion barrier and disrupts the integrity of the molecular composition in the primary cilium, which may contribute to alterations in neuroarchitecture.
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المشرفين على المادة: 0 (Antigens, Neoplasm)
0 (Cell Cycle Proteins)
0 (Cep290 protein, human)
0 (Cytoskeletal Proteins)
0 (Hedgehog Proteins)
0 (Patched-1 Receptor)
0 (Ptch1 protein, mouse)
0 (SHH protein, human)
0 (Shh protein, mouse)
0 (Smo protein, mouse)
0 (Smoothened Receptor)
تواريخ الأحداث: Date Created: 20181128 Date Completed: 20191209 Latest Revision: 20240309
رمز التحديث: 20240309
مُعرف محوري في PubMed: PMC6255789
DOI: 10.1038/s41598-018-35614-x
PMID: 30478281
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-018-35614-x