A role for OCRL in glomerular function and disease

TY - JOUR

T1 - A role for OCRL in glomerular function and disease

AU - Preston, Rebecca

AU - Naylor, Richard W.

AU - Stewart, Graham

AU - Bierzynska, Agnieszka

AU - Saleem, Moin A.

AU - Lowe, Martin

AU - Lennon, Rachel

N1 - Funding for this research was provided by: Wellcome Trust (202860/Z/16/Z) National Institute for Health Research Lowe Syndrome Trust (ML/MU/2012)

PY - 2020/4

Y1 - 2020/4

N2 - 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.

AB - 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.

KW - FSGS

KW - Glomerular disease

KW - Lowe syndrome

KW - OCRL

KW - Podocyte

KW - Proteinuria

UR - https://www.scopus.com/pages/publications/85076135932

U2 - 10.1007/s00467-019-04317-4

DO - 10.1007/s00467-019-04317-4

M3 - Article

C2 - 31811534

SN - 0931-041X

SP - 641

EP - 648

JO - Pediatric Nephrology

JF - Pediatric Nephrology

ER -