KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy‐lysosome defect
| العنوان: | KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy‐lysosome defect |
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| المؤلفون: | James A. Wohlschlegel, Jill A. Rosenfeld, Isabelle Coppens, Janet Markle, Marsha Pratt, Nawal Makhseed, Xianghui Chen, Thomas A. Burrow, Yu Zhang, Timothy S. Wang, Santosh R. Mordekar, Noelle R. Danylchuk, Michael E. Meadow, Kyle Metz, Daniel Crooks, Satish Agadi, Katrina Peariso, Gerard T. Berry, Michael J. Parker, Hee Jong Kim, Esther Leshinsky-Silver, Dianalee McKnight, Christine Stanley, Tobias Loddenkemper, Adam L. Hartman, Isabelle Prehl, Gustavo Maegawa, J. Marie Hardwick, Adolfo Garnica, Abdel Aouacheria, Min Tsui Ong, Parul Jayakar, Weimin Bi, Heather M. Lamb, Hatha Gbedawo, Michael Alber, Bart E. Wagner, Thomas C. Markello, Yaping Yang, Glenn Anderson, Xinchen Teng, Edda Haberlandt, Pankaj B. Agrawal |
| المساهمون: | Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), R01 NS037402/NH/NIH HHS/United StatesR01 NS083373/NH/NIH HHS/United StatesT32 AI007417/AI/NIAID NIH HHS/United StatesCURE/CURE, Citizens United for Research in Epilepsy/United StatesR01 NS037402/NS/NINDS NIH HHS/United StatesR21 NS096677/NS/NINDS NIH HHS/United StatesK08 NS070931/NS/NINDS NIH HHS/United StatesK08 NS070931/NH/NIH HHS/United StatesR01 GM077875/GM/NIGMS NIH HHS/United StatesR01 GM089778/GM/NIGMS NIH HHS/United StatesR01 GM089778/NH/NIH HHS/United StatesR01 NS083373/NS/NINDS NIH HHS/United States, Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE) |
| المصدر: | Annals of Neurology Annals of Neurology, 2018, 84 (5), pp.766-780. ⟨10.1002/ana.25351⟩ Annals of Neurology, Wiley, 2018, 84 (5), pp.766-780. ⟨10.1002/ana.25351⟩ |
| بيانات النشر: | Wiley, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Potassium Channels, Movement disorders, MESH: Lysosomes/pathology, KCTD7, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH: Potassium Channels/deficiency, MESH: Lysosomes/genetics, MESH: Neurodegenerative Diseases/pathology, Age of Onset, Genetics, Neurodegenerative Diseases, MESH: Infant, Pedigree, 3. Good health, medicine.anatomical_structure, Neurology, Child, Preschool, Female, MESH: Autophagy/genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Saccharomyces cerevisiae Proteins, MESH: Mutation, Protein family, MESH: Pedigree, MESH: Age of Onset, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Progressive myoclonus epilepsy, Biology, Article, Lipofuscin, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Lysosome, Autophagy, medicine, Humans, MESH: Neurodegenerative Diseases/genetics, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Potassium Channels/genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Child, Preschool, Infant, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Male, MESH: Saccharomyces cerevisiae Proteins/genetics, 030104 developmental biology, Mutation, Neuronal ceroid lipofuscinosis, Neurology (clinical), Age of onset, Lysosomes, MESH: Female |
| الوصف: | International audience; OBJECTIVE:Several small case series identified KCTD7 mutations in patients with a rare autosomal recessive disorder designated progressive myoclonic epilepsy (EPM3) and neuronal ceroid lipofuscinosis (CLN14). Despite the name KCTD (potassium channel tetramerization domain), KCTD protein family members lack predicted channel domains. We sought to translate insight gained from yeast studies to uncover disease mechanisms associated with deficiencies in KCTD7 of unknown function.METHODS:Novel KCTD7 variants in new and published patients were assessed for disease causality using genetic analyses, cell-based functional assays of patient fibroblasts and knockout yeast, and electron microscopy of patient samples.RESULTS:Patients with KCTD7 mutations can exhibit movement disorders or developmental regression before seizure onset, and are distinguished from similar disorders by an earlier age of onset. Although most published KCTD7 patient variants were excluded from a genome sequence database of normal human variations, most newly identified patient variants are present in this database, potentially challenging disease causality. However, genetic analysis and impaired biochemical interactions with cullin 3 support a causal role for patient KCTD7 variants, suggesting deleterious alleles of KCTD7 and other rare disease variants may be underestimated. Both patient-derived fibroblasts and yeast lacking Whi2 with sequence similarity to KCTD7 have impaired autophagy consistent with brain pathology.INTERPRETATION:Biallelic KCTD7 mutations define a neurodegenerative disorder with lipofuscin and lipid droplet accumulation but without defining features of neuronal ceroid lipofuscinosis or lysosomal storage disorders. KCTD7 deficiency appears to cause an underlying autophagy-lysosome defect conserved in yeast, thereby assigning a biological role for KCTD7. |
| تدمد: | 1531-8249 0364-5134 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e934647c53095a558f35a183951ec7eeTest https://doi.org/10.1002/ana.25351Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e934647c53095a558f35a183951ec7ee |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15318249 03645134 |
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