Effects of Proximal Tubule Shortening on Protein Excretion in a Lowe Syndrome Model

J Am Soc Nephrol. 2020 Jan;31(1):67-83. doi: 10.1681/ASN.2019020125. Epub 2019 Nov 1.


Background: Lowe syndrome (LS) is an X-linked recessive disorder caused by mutations in OCRL, which encodes the enzyme OCRL. Symptoms of LS include proximal tubule (PT) dysfunction typically characterized by low molecular weight proteinuria, renal tubular acidosis (RTA), aminoaciduria, and hypercalciuria. How mutant OCRL causes these symptoms isn't clear.

Methods: We examined the effect of deleting OCRL on endocytic traffic and cell division in newly created human PT CRISPR/Cas9 OCRL knockout cells, multiple PT cell lines treated with OCRL-targeting siRNA, and in orcl-mutant zebrafish.

Results: OCRL-depleted human cells proliferated more slowly and about 10% of them were multinucleated compared with fewer than 2% of matched control cells. Heterologous expression of wild-type, but not phosphatase-deficient, OCRL prevented the accumulation of multinucleated cells after acute knockdown of OCRL but could not rescue the phenotype in stably edited knockout cell lines. Mathematic modeling confirmed that reduced PT length can account for the urinary excretion profile in LS. Both ocrl mutant zebrafish and zebrafish injected with ocrl morpholino showed truncated expression of megalin along the pronephric kidney, consistent with a shortened S1 segment.

Conclusions: Our data suggest a unifying model to explain how loss of OCRL results in tubular proteinuria as well as the other commonly observed renal manifestations of LS. We hypothesize that defective cell division during kidney development and/or repair compromises PT length and impairs kidney function in LS patients.

Keywords: Fanconi syndrome; OCRL; megalin; mitosis; phosphatidylinositol 4,5-bisphosphate; proximal tubule.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Humans
  • Kidney Tubules, Proximal / physiology*
  • Models, Biological
  • Mutation
  • Oculocerebrorenal Syndrome / genetics
  • Oculocerebrorenal Syndrome / metabolism*
  • Phosphoric Monoester Hydrolases / genetics
  • Proteins / metabolism*


  • Proteins
  • Phosphoric Monoester Hydrolases
  • OCRL protein, human