Loss of Cajal Bodies in Motor Neurons from patients with novel mutations in VRK1
| العنوان: | Loss of Cajal Bodies in Motor Neurons from patients with novel mutations in VRK1 |
|---|---|
| المؤلفون: | Marc Bartoli, Salam Koussa, Nathalie Bernard-Marissal, Rosette Jabbour, Khalil Rihan, Christel Castro, André Mégarbané, Valérie Delague, Nicolas Lévy, Lara El-Bazzal, Alexandre Atkinson, Jean-Pierre Desvignes, Eliane Chouery-Khoury, Karine Bertaux |
| المساهمون: | Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Médicale, Université Saint-Joseph de Beyrouth (USJ), Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Department of Neurology, Lebanese University Hospital-Geitaoui, Institut Jérôme Lejeune, Centre Médical et Psychopédagogique (CEMEDDIP), University of Balamand [Liban] (UOB), delague, valérie, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Balamand - UOB (LIBAN) |
| المصدر: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2019, ⟨10.1093/hmg/ddz060⟩ |
| بيانات النشر: | HAL CCSD, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, relationship - sibling, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, Compound heterozygosity, 0302 clinical medicine, neuritis, genes, Genetics (clinical), Mutation, phosphorylation, catabolism, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, General Medicine, Middle Aged, Phenotype, motor, medicine.anatomical_structure, cytoplasm, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Coilin, Proteasome Inhibitors, Adult, Neurite, phenotype, Induced Pluripotent Stem Cells, Protein Serine-Threonine Kinases, Biology, 03 medical and health sciences, fibroblasts, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Exome Sequencing, Genetics, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Humans, nervous system disorders, motor neurons, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Motor Neuron Disease, Molecular Biology, vaccinia, [SDV.GEN]Life Sciences [q-bio]/Genetics, cell nucleus, Motor neuron, heterozygote, Cell nucleus, 030104 developmental biology, Cajal body, coiled bodies, phosphotransferases, mutation, Protein Processing, Post-Translational, Neuroscience, 030217 neurology & neurosurgery |
| الوصف: | Distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of diseases, resembling Charcot–Marie–Tooth syndromes, but characterized by an exclusive involvement of the motor part of the peripheral nervous system. Here, we describe two new compound heterozygous mutations in VRK1, the vaccinia-related kinase 1 gene, in two siblings from a Lebanese family, affected with dHMN associated with upper motor neurons (MNs) signs. The mutations lead to severely reduced levels of VRK1 by impairing its stability, and to a shift of nuclear VRK1 to cytoplasm. Depletion of VRK1 from the nucleus alters the dynamics of coilin, a phosphorylation target of VRK1, by reducing its stability through increased proteasomal degradation. In human-induced pluripotent stem cell-derived MNs from patients, we demonstrate that this drop in VRK1 levels leads to Cajal bodies (CBs) disassembly and to defects in neurite outgrowth and branching. Mutations in VRK1 have been previously reported in several neurological diseases affecting lower or both upper and lower MNs. Here, we describe a new phenotype linked to VRK1 mutations, presenting as a classical slowly progressive motor neuropathy, beginning in the second decade of life, with associated upper MN signs. We provide, for the first time, evidence for a role of VRK1 in regulating CB assembly in MNs. The observed MN defects are consistent with a length dependent axonopathy affecting lower and upper MNs, and we propose that diseases due to mutations in VRK1 should be grouped under a unique entity named `VRK1-related motor neuron disease’. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0964-6906 1460-2083 |
| DOI: | 10.1093/hmg/ddz060⟩ |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::379ad8ce8f9b1eb0c81979c36fc1c62a https://hal-amu.archives-ouvertes.fr/hal-02152040/document |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....379ad8ce8f9b1eb0c81979c36fc1c62a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 09646906 14602083 |
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| DOI: | 10.1093/hmg/ddz060⟩ |