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 Navarro, Anna
- dc.date.accessioned 2022-03-25T07:06:05Z
- dc.date.available 2022-03-25T07:06:05Z
- dc.date.issued 2021
- 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.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.doi http://dx.doi.org/10.1093/hmg/ddab131
- dc.identifier.issn 0964-6906
- dc.identifier.uri http://hdl.handle.net/10230/52772
- dc.language.iso eng
- dc.publisher Oxford University Press
- dc.relation.ispartof Hum Mol Genet. 2021 Jul 9;30(15):1413-28
- 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 © 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.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- 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.title Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion