Identification of novel OCRL isoforms associated with phenotypic differences between Dent disease-2 and Lowe syndrome

Nephrol Dial Transplant. 2022 Jan 25;37(2):262-270. doi: 10.1093/ndt/gfab274.


Background: Although Lowe syndrome and Dent disease-2 are caused by Oculocerebrorenal syndrome of Lowe (OCRL) mutations, their clinical severities differ substantially and their molecular mechanisms remain unclear. Truncating mutations in OCRL exons 1-7 lead to Dent disease-2, whereas those in exons 8-24 lead to Lowe syndrome. Herein we identified the mechanism underlying the action of novel OCRL protein isoforms.

Methods: Messenger RNA samples extracted from cultured urine-derived cells from a healthy control and a Dent disease-2 patient were examined to detect the 5' end of the OCRL isoform. For protein expression and functional analysis, vectors containing the full-length OCRL transcripts, the isoform transcripts and transcripts with truncating mutations detected in Lowe syndrome and Dent disease-2 patients were transfected into HeLa cells.

Results: We successfully cloned the novel isoform transcripts from OCRL exons 6-24, including the translation-initiation codons present in exon 8. In vitro protein-expression analysis detected proteins of two different sizes (105 and 80 kDa) translated from full-length OCRL, whereas only one protein (80 kDa) was found from the isoform and Dent disease-2 variants. No protein expression was observed for the Lowe syndrome variants. The isoform enzyme activity was equivalent to that of full-length OCRL; the Dent disease-2 variants retained >50% enzyme activity, whereas the Lowe syndrome variants retained <20% activity.

Conclusions: We elucidated the molecular mechanism underlying the two different phenotypes in OCRL-related diseases; the functional OCRL isoform translated starting at exon 8 was associated with this mechanism.

Keywords: Dent disease-2; Lowe syndrome, OCRL; PI(4,5)P2 5-phosphatase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dent Disease* / diagnosis
  • Dent Disease* / genetics
  • HeLa Cells
  • Humans
  • Mutation / genetics
  • Oculocerebrorenal Syndrome* / diagnosis
  • Oculocerebrorenal Syndrome* / genetics
  • Phenotype
  • Phosphoric Monoester Hydrolases* / genetics
  • Protein Isoforms / genetics


  • Protein Isoforms
  • Phosphoric Monoester Hydrolases
  • OCRL protein, human