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Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function

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dc.contributor.author Durán, Mónica
dc.contributor.author Burballa Tàrrega, Carla, 1988-
dc.contributor.author Cantero Recasens, Gerard, 1984-
dc.contributor.author Butnaru, Cristian M.
dc.contributor.author Malhotra, Vivek
dc.contributor.author Ariceta, Gema
dc.contributor.author Sarró, Eduard
dc.contributor.author Meseguer, Anna
dc.date.accessioned 2022-03-25T07:06:05Z
dc.date.available 2022-03-25T07:06:05Z
dc.date.issued 2021
dc.identifier.citation Durán M, Burballa C, Cantero-Recasens G, Butnaru CM, Malhotra V, Ariceta G et al. Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function. Hum Mol Genet. 2021 Jul 9;30(15):1413-28. DOI: 10.1093/hmg/ddab131
dc.identifier.issn 0964-6906
dc.identifier.uri http://hdl.handle.net/10230/52772
dc.description.abstract Dent disease 1 (DD1) is a rare X-linked renal proximal tubulopathy characterized by low molecular weight proteinuria and variable degree of hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressing to chronic kidney disease. Although mutations in the electrogenic Cl-/H+ antiporter ClC-5, which impair endocytic uptake in proximal tubule cells, cause the disease, there is poor genotype-phenotype correlation and their contribution to proximal tubule dysfunction remains unclear. To further discover the mechanisms linking ClC-5 loss-of-function to proximal tubule dysfunction, we have generated novel DD1 cellular models depleted of ClC-5 and carrying ClC-5 mutants p.(Val523del), p.(Glu527Asp) and p.(Ile524Lys) using the human proximal tubule-derived RPTEC/TERT1 cell line. Our DD1 cellular models exhibit impaired albumin endocytosis, increased substrate adhesion and decreased collective migration, correlating with a less differentiated epithelial phenotype. Despite sharing functional features, these DD1 cell models exhibit different gene expression profiles, being p.(Val523del) ClC-5 the mutation showing the largest differences. Gene set enrichment analysis pointed to kidney development, anion homeostasis, organic acid transport, extracellular matrix organization and cell-migration biological processes as the most likely involved in DD1 pathophysiology. In conclusion, our results revealed the pathways linking ClC-5 mutations with tubular dysfunction and, importantly, provide new cellular models to further study DD1 pathophysiology.
dc.description.sponsorship This work was supported in part by Asdent Patients Association and grants from Ministerio de Ciencia e Innovación (SAF201459945-R and SAF201789989-R to A.M.), the Fundación Senefro (SEN2019 to A.M.) and Red de Investigación Renal REDinREN (12/0021/0013). A.M. group holds the Quality Mention from the Generalitat de Catalunya (2017 SGR).
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Oxford University Press
dc.relation.ispartof Hum Mol Genet. 2021 Jul 9;30(15):1413-28
dc.rights © The Author(s) 2021. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1093/hmg/ddab131
dc.subject.keyword Phenotype
dc.subject.keyword Proteinuria
dc.subject.keyword Mutation
dc.subject.keyword Cell proliferation
dc.subject.keyword Extracellular matrix
dc.subject.keyword Albumins
dc.subject.keyword Kidney failure
dc.subject.keyword Chronic
dc.subject.keyword Epithelium
dc.subject.keyword Homeostasis
dc.subject.keyword Hypercalciuria
dc.subject.keyword Adhesions
dc.subject.keyword Anions
dc.subject.keyword Antiporter
dc.subject.keyword Cell lines
dc.subject.keyword Cell motility
dc.subject.keyword Endocytosis
dc.subject.keyword Gene expression profiling
dc.subject.keyword Genes
dc.subject.keyword Kidney tubules
dc.subject.keyword Proximal
dc.subject.keyword Molecular mass
dc.subject.keyword Nephrocalcinosis
dc.subject.keyword Kidney
dc.subject.keyword Nephrolithiasis
dc.subject.keyword X-linked inheritance
dc.subject.keyword Dent's disease
dc.subject.keyword Acids
dc.subject.keyword Organic genotype-phenotype associations
dc.subject.keyword Kidney development
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-59945-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-89989-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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