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 |