Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies.
CLCN5 gene mutations
cubilin
dent disease
immunohistochemistry
kidney biopsies
megalin
proximal tubular ClC-5 expression
whole exome sequencing
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
14 01 2020
14 01 2020
Historique:
received:
04
12
2019
revised:
08
01
2020
accepted:
10
01
2020
entrez:
18
1
2020
pubmed:
18
1
2020
medline:
7
10
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31947599
pii: ijms21020516
doi: 10.3390/ijms21020516
pmc: PMC7014080
pii:
doi:
Substances chimiques
Biomarkers
0
CLC-5 chloride channel
0
Chloride Channels
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : U54 DK083908
Pays : United States
Organisme : Università degli Studi di Padova
ID : STPD11F33L
Pays : International
Organisme : NCATS NIH HHS
ID : U54DK83908
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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