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Open AccessArticle

Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

1
Laboratory of Histomorphology and Molecular Biology of the Kidney, Clinical Nephrology, Department of Medicine—DIMED, University of Padua, 35128 Padua, Italy
2
CRIBI Biotechnology Centre, University of Padua, 35131 Padua, Italy
3
Pediatric Nephrology, Dialysis and Transplant Unit, Department of Women’s and Children’s Health, Padua University Hospital, 35128 Padua, Italy
4
Pediatric Nephrology Unit, Regina Margherita Children’s Hospital, 10126 CDSS Turin, Italy
5
Pediatric Nephrology Unit, University Hospital, P.O. Giovanni XXIII, 70126 Bari, Italy
6
Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS, Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
7
Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Membership of the Dent Disease Italian Network is provided in the Acknowledgments.
Int. J. Mol. Sci. 2020, 21(2), 516; https://doi.org/10.3390/ijms21020516 (registering DOI)
Received: 4 December 2019 / Revised: 8 January 2020 / Accepted: 10 January 2020 / Published: 14 January 2020
Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC-5 and of megalin and cubilin receptors in DD1 kidney biopsies. About 25% of DD cases lack mutations in either CLCN5 or OCRL genes (DD3), and no other disease genes have been discovered so far. Sanger sequencing was used for CLCN5 gene analysis in 158 unrelated males clinically suspected of having DD. The tubular expression of ClC-5, megalin, and cubilin was assessed by immunolabeling in 10 DD1 kidney biopsies. Whole exome sequencing (WES) was performed in eight DD3 patients. Twenty-three novel CLCN5 mutations were identified. ClC-5, megalin, and cubilin were significantly lower in DD1 than in control biopsies. The tubular expression of ClC-5 when detected was irrespective of the type of mutation. In four DD3 patients, WES revealed 12 potentially pathogenic variants in three novel genes (SLC17A1, SLC9A3, and PDZK1), and in three genes known to be associated with monogenic forms of renal proximal tubulopathies (SLC3A, LRP2, and CUBN). The supposed third Dent disease-causing gene was not discovered. View Full-Text
Keywords: dent disease; CLCN5 gene mutations; proximal tubular ClC-5 expression; megalin; cubilin; kidney biopsies; immunohistochemistry; whole exome sequencing dent disease; CLCN5 gene mutations; proximal tubular ClC-5 expression; megalin; cubilin; kidney biopsies; immunohistochemistry; whole exome sequencing
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Gianesello, L.; Ceol, M.; Bertoldi, L.; Terrin, L.; Priante, G.; Murer, L.; Peruzzi, L.; Giordano, M.; Paglialonga, F.; Cantaluppi, V.; Musetti, C.; Valle, G.; Del Prete, D.; Anglani, F.; Dent Disease Italian Network. Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies. Int. J. Mol. Sci. 2020, 21, 516.

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