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 (Peer-Reviewed Journal) 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, 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


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.