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J Am Soc Nephrol. 2016 Nov 28. pii: ASN.2016080913. [Epub ahead of print]

Kidney Tubular Ablation of Ocrl/Inpp5b Phenocopies Lowe Syndrome Tubulopathy.

Inoue K1, Balkin DM2,3,4, Liu L2,3,4,5, Nandez R2,3,4, Wu Y2,3,4,5, Tian X1, Wang T6, Nussbaum R7,8,3, De Camilli P9,3,4,5, Ishibe S10,6.

Author information

  • 1Departments of Internal Medicine.
  • 2Cell Biology.
  • 3Howard Hughes Medical Institute, and.
  • 4Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, Connecticut.
  • 5Neuroscience, and.
  • 6Cellular and Molecular Physiology.
  • 7Department of Medicine and.
  • 8Institute of Human Genetics, University of California, San Francisco, California; and.
  • 9Cell Biology,
  • 10Departments of Internal Medicine,


Lowe syndrome and Dent disease are two conditions that result from mutations of the inositol 5-phosphatase oculocerebrorenal syndrome of Lowe (OCRL) and share the feature of impaired kidney proximal tubule function. Genetic ablation of Ocrl in mice failed to recapitulate the human phenotypes, possibly because of the redundant functions of OCRL and its paralog type 2 inositol polyphosphate-5-phosphatase (INPP5B). Germline knockout of both paralogs in mice results in early embryonic lethality. We report that kidney tubule-specific inactivation of Inpp5b on a global Ocrl-knockout mouse background resulted in low molecular weight proteinuria, phosphaturia, and acidemia. At the cellular level, we observed a striking impairment of clathrin-dependent and -independent endocytosis in proximal tubules, phenocopying what has been reported for Dent disease caused by mutations in the gene encoding endosomal proton-chloride exchange transporter 5. These results suggest that the functions of OCRL/INPP5B and proton-chloride exchange transporter 5 converge on shared mechanisms, the impairment of which has a dramatic effect on proximal tubule endocytosis.


INPP5B; Lowe syndrome; OCRL; endocytosis; proximal tubulopathy

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