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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Derived From Structural and Functional Analysis of 14 ClC-7 Mutants
Journal of Bone and Mineral Research, Volume 36, No. 3, Year 2021
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Description
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).
Authors & Co-Authors
Di Zanni, Eleonora
Italy, Rome
Consiglio Nazionale Delle Ricerche
Palagano, Eleonora
Italy, Monserrato
Cnr Istituto Di Ricerca Genetica e Biomedica
Italy, Rozzano
Humanitas Research Hospital
Lagostena, Laura
Italy, Rome
Consiglio Nazionale Delle Ricerche
Strina, Dario
Italy, Monserrato
Cnr Istituto Di Ricerca Genetica e Biomedica
Italy, Rozzano
Humanitas Research Hospital
Rehman, Asma
United States, Baltimore
University of Maryland, Baltimore Umb
Abinun, Mario A.
United Kingdom, Newcastle
Great North Children's Hospital
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
de Somer, Lien
Belgium, Leuven
Ku Leuven– University Hospital Leuven
Martire, Baldassarre
Italy
“monsignor Dimiccoli” Hospital
Brown, Justin
Australia, Clayton
Monash University
Australia, Clayton
Monash Children's Hospital
Kariminejad, Ariana
Iran, Tehran
Kariminejad-najmabadi Pathology and Genetics Center
Balasubramaniam, Shanti
Australia, Perth
Perth Children's Hospital
Baynam, Gareth S.
Australia, Perth
King Edward Memorial Hospital for Women
Australia, Perth
Telethon Kids Institute
Australia, Fremantle
The University of Notre Dame Australia
Gurrieri, Fiorella
Italy, Rome
Università Campus Bio-medico Di Roma
Pisanti, Maria A.
Italy, Naples
Azienda Ospedaliera Di Rilievo Nazionale Antonio Cardarelli
De Maggio, Ilaria
Italy, Naples
Azienda Ospedaliera Di Rilievo Nazionale Antonio Cardarelli
Abboud, Miguel Raul
Lebanon, Beirut
American University of Beirut Medical Center
Chiesa, Robert
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Burren, C. P.
United Kingdom, Bristol
Bristol Royal Hospital for Children
United Kingdom, Bristol
Bristol Medical School
Villa, Anna
Italy, Monserrato
Cnr Istituto Di Ricerca Genetica e Biomedica
Italy, Milan
San Raffaele Telethon Institute for Gene Therapy
Sobacchi, Cristina
Italy, Monserrato
Cnr Istituto Di Ricerca Genetica e Biomedica
Italy, Rozzano
Humanitas Research Hospital
Picollo, Alessandra
Italy, Rome
Consiglio Nazionale Delle Ricerche
Statistics
Citations: 21
Authors: 21
Affiliations: 22
Identifiers
Doi:
10.1002/jbmr.4200
ISSN:
08840431
e-ISSN:
15234681
Research Areas
Cancer
Genetics And Genomics