A role for OCRL in glomerular function and disease

Pediatr Nephrol. 2020 Apr;35(4):641-648. doi: 10.1007/s00467-019-04317-4. Epub 2019 Dec 6.

Abstract

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.

Keywords: FSGS; Glomerular disease; Lowe syndrome; OCRL; Podocyte; Proteinuria.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Child
  • Chloride Channels
  • Glomerulosclerosis, Focal Segmental / complications
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Humans
  • Kidney Glomerulus / metabolism*
  • Male
  • Mutation
  • Oculocerebrorenal Syndrome / complications
  • Oculocerebrorenal Syndrome / genetics*
  • Phosphoric Monoester Hydrolases
  • Podocytes / metabolism
  • Proteinuria / etiology
  • Whole Exome Sequencing
  • Zebrafish

Substances

  • CLC-5 chloride channel
  • Chloride Channels
  • Phosphoric Monoester Hydrolases
  • OCRL protein, human