Novel OCRL1 mutations in patients with the phenotype of dent disease

Utsch B., Boekenkamp A., Benz M. R., Besbas N., Doetsch J., Franke I., ...More

AMERICAN JOURNAL OF KIDNEY DISEASES, vol.48, no.6, pp.942-954, 2006 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 48 Issue: 6
  • Publication Date: 2006
  • Doi Number: 10.1053/j.ajkd.2006.08.018
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.942-954
  • Keywords: dent disease, Lowe syndrome, voltage-gated chloride channel and chloride/proton antiporter 5-, -gene (CLCN5), oculocerebrorenal syndrome of Lowe gene (OCRL1), tubulopathy, cataract, mental retardation, creatine kinase (CK), lactate clehydrogenase (LDH)., LOWE OCULOCEREBRORENAL SYNDROME, INOSITOL POLYPHOSPHATE 5-PHOSPHATASE, CHLORIDE CHANNEL, CLC PROTEINS, GENE, IDENTIFICATION, DEFICIENCY, FAMILIES, CELLS, NEPHROLITHIASIS
  • Hacettepe University Affiliated: Yes


Background: Dent disease is an X-linked tubulopathy frequently caused by mutations affecting the voltage-gated chloride channel and chloride/proton antiporter CIC-5. A recent study showed that defects in OCRL1, encoding a phosphatidylinositol 4,5-bisphosphate 5-phosphatase (Ocrl) and usually found mutated in patients with Lowe syndrome, also can provoke a Dent-like phenotype (Dent 2 disease). Methods: We investigated 20 CLCN5-negative males from 17 families with a phenotype resembling Dent disease for defects in OCRL1. Results: In our complete series of 35 families with a phenotype of Dent disease, a mutation in the OCRL 1 gene was detected in 6 kindreds. All were novel frameshift (Q70RfsX88 and T121NfsX122, detected twice) or missense mutations (1257T and R476W). None of our patients had cognitive or behavioral impairment or cataracts, 2 classic hallmarks of Lowe syndrome. All patients had mild increases in lactate dehydrogenase and/or creatine kinase levels, which rarely is observed in CLCN5-positive patients, but frequently found in patients with Lowe syndrome. To explain the phenotypic heterogeneity caused by OCRL1 mutations, we performed extensive data-bank mining and extended reverse-transcriptase polymerase chain reaction analysis, which provided no evidence for yet unknown (tissue-specific) alternative OCRL1 transcripts. Conclusion: Mutations in the OCRL1 gene are found in approximately 23% of kindreds with a Dent phenotype. Defective protein sorting/targeting of Ocrl might be the reason for mildly elevated creatine kinase and lactate dehydrogenase serum concentrations in these patients and a clue to suspect Dent disease unrelated to CLCN5 mutations. It remains to be elucidated why the various OCRL1 mutations found in patients with Dent 2 disease do not cause cataracts.