Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Derived from Structural and Functional Analysis of 14 ClC-7 Mutants
| Autor: | Shanti Balasubramanian, Miguel R. Abboud, Cristina Sobacchi, Maria Antonietta Pisanti, Baldassarre Martire, Robert Chiesa, Laura Lagostena, Fiorella Gurrieri, Ariana Kariminejad, Dario Strina, Gareth Baynam, Eleonora Di Zanni, Asma Rehman, Alessandra Picollo, Christine P Burren, Lien De Somer, Eleonora Palagano, Ilaria De Maggio, Justin C. Brown, Anna Villa, Mario Abinun |
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| Jazyk: | English, Middle (1100-1500) |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Protein family Endocrinology Diabetes and Metabolism Osteoclasts 030209 endocrinology & metabolism medicine.disease_cause 03 medical and health sciences Mice missense mutations 0302 clinical medicine Osteoclast Chloride Channels medicine Lysosomal storage disease Animals Humans Orthopedics and Sports Medicine Bone Resorption Cellular localization Mutation biology urogenital system Neurodegeneration Osteopetrosis chloride-proton exchanger medicine.disease Cell biology 030104 developmental biology medicine.anatomical_structure lysosomal localization osteoclast biology.protein osteopetrosis CLC-7 CLCN7 Lysosomes |
| Zdroj: | Journal of bone and mineral research 36 (2020): 535–541. doi:10.1002/jbmr.4200 info:cnr-pdr/source/autori:Eleonora Di Zanni 1, Eleonora Palagano 2 3, Laura Lagostena 1, Dario Strina 2 3, Asma Rehman 4, Mario Abinun 5 6, Lien De Somer 7, Baldassarre Martire 8, Justin Brown 9 10, Ariana Kariminejad 11, Shanti Balasubramanian 12, Gareth Baynam 13 14 15 16, Fiorella Gurrieri 17, Maria A Pisanti 18, Ilaria De Maggio 18, Miguel R Abboud 19, Robert Chiesa 20, Christine P Burren 21 22, Anna Villa 2 23, Cristina Sobacchi 2 3, Alessandra Picollo 1/titolo:Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Derived from Structural and Functional Analysis of 14 ClC-7 Mutants/doi:10.1002%2Fjbmr.4200/rivista:Journal of bone and mineral research/anno:2020/pagina_da:535/pagina_a:541/intervallo_pagine:535–541/volume:36 Di Zanni, E, Palagano, E, Lagostena, L, Strina, D, Rehman, A, Abinun, M, De Somer, L, Martire, B, Brown, J, Kariminejad, A, Balasubramanian, S, Baynam, G, Gurrieri, F, Pisanti, M A, De Maggio, I, Abboud, M R, Chiesa, R, Burren, C P, Villa, A, Sobacchi, C & Picollo, A 2020, ' Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Derived from Structural and Functional Analysis of 14 ClC-7 Mutants ', Journal of Bone and Mineral Research . https://doi.org/10.1002/jbmr.4200 |
| DOI: | 10.1002/jbmr.4200 |
| Popis: | ClC-7 is a chloride-proton antiporter of the CLC protein family. In complex with its accessory protein Ostm-1, ClC-7 localizes to lysosomes and to the osteoclasts' ruffled border, where it plays a critical role in acidifying the resorption lacuna during bone resorption. Gene inactivation in mice causes severe osteopetrosis, neurodegeneration, and lysosomal storage disease. Mutations in the human CLCN7 gene are associated with diverse forms of osteopetrosis. The functional evaluation of ClC-7 variants might be informative with respect to their pathogenicity, but the cellular localization of the protein hampers this analysis. Here we investigated the functional effects of 13 CLCN7 mutations identified in 13 new patients with severe or mild osteopetrosis and a known ADO2 mutation. We mapped the mutated amino acid residues in the homology model of ClC-7 protein, assessed the lysosomal colocalization of ClC-7 mutants and Ostm1 through confocal microscopy, and performed patch-clamp recordings on plasma-membrane-targeted mutant ClC-7. Finally, we analyzed these results together with the patients' clinical features and suggested a correlation between the lack of ClC-7/Ostm1 in lysosomes and severe neurodegeneration. © 2020 American Society for Bone and Mineral Research (ASBMR). |
| Databáze: | OpenAIRE |
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