A role for OCRL in glomerular function and disease.
FSGS
Glomerular disease
Lowe syndrome
OCRL
Podocyte
Proteinuria
Journal
Pediatric nephrology (Berlin, Germany)
ISSN: 1432-198X
Titre abrégé: Pediatr Nephrol
Pays: Germany
ID NLM: 8708728
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
03
09
2018
accepted:
23
07
2019
revised:
15
07
2019
pubmed:
8
12
2019
medline:
1
4
2021
entrez:
8
12
2019
Statut:
ppublish
Résumé
Lowe syndrome and Dent-2 disease are caused by mutations in the OCRL gene, which encodes for an inositol 5-phosphatase. The renal phenotype associated with OCRL mutations typically comprises a selective proximal tubulopathy, which can manifest as Fanconi syndrome in the most extreme cases. Here, we report a 12-year-old male with nephrotic-range proteinuria and focal segmental glomerulosclerosis on renal biopsy. As a glomerular pathology was suspected, extensive investigation of tubular function was not performed. Surprisingly, whole exome sequencing identified a genetic variant in OCRL (c1467-2A>G) that introduced a novel splice mutation leading to skipping of exon 15. In situ hybridisation of adult human kidney tissue and zebrafish larvae showed OCRL expression in the glomerulus, supporting a role for OCRL in glomerular function. In cultured podocytes, we found that OCRL associated with the linker protein IPIP27A and CD2AP, a protein that is important for maintenance of the podocyte slit diaphragm. Taken together, this work suggests a previously under-appreciated role for OCRL in glomerular function and highlights the importance of investigating tubular function in patients with persistent proteinuria.
Sections du résumé
BACKGROUND
Lowe syndrome and Dent-2 disease are caused by mutations in the OCRL gene, which encodes for an inositol 5-phosphatase. The renal phenotype associated with OCRL mutations typically comprises a selective proximal tubulopathy, which can manifest as Fanconi syndrome in the most extreme cases.
METHODS
Here, we report a 12-year-old male with nephrotic-range proteinuria and focal segmental glomerulosclerosis on renal biopsy. As a glomerular pathology was suspected, extensive investigation of tubular function was not performed.
RESULTS
Surprisingly, whole exome sequencing identified a genetic variant in OCRL (c1467-2A>G) that introduced a novel splice mutation leading to skipping of exon 15. In situ hybridisation of adult human kidney tissue and zebrafish larvae showed OCRL expression in the glomerulus, supporting a role for OCRL in glomerular function. In cultured podocytes, we found that OCRL associated with the linker protein IPIP27A and CD2AP, a protein that is important for maintenance of the podocyte slit diaphragm.
CONCLUSION
Taken together, this work suggests a previously under-appreciated role for OCRL in glomerular function and highlights the importance of investigating tubular function in patients with persistent proteinuria.
Identifiants
pubmed: 31811534
doi: 10.1007/s00467-019-04317-4
pii: 10.1007/s00467-019-04317-4
pmc: PMC7056711
doi:
Substances chimiques
CLC-5 chloride channel
0
Chloride Channels
0
Phosphoric Monoester Hydrolases
EC 3.1.3.2
OCRL protein, human
EC 3.1.3.36
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
641-648Subventions
Organisme : Medical Research Council
ID : G0800571
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800200
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P024297/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 202860/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R013942/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R003017/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203128/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L002418/1
Pays : United Kingdom
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