title: Novel OCRL1 mutations in patients with the phenotype of Dent disease.
abstract: BACKGROUND
  Dent disease is an X-linked tubulopathy frequently caused by mutations affecting the voltage-gated chloride channel and chloride/proton antiporter ClC-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 OCRL1 gene was detected in 6 kindreds. All were novel frameshift (Q70RfsX88 and T121NfsX122, detected twice) or missense mutations (I257T 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Klinik mit Poliklinik für Kinder und Jugendliche, Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Utsch
authors.forename: Arend
authors.initials: A
authors.lastname: Bökenkamp
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Benz
authors.forename: Nesrin
authors.initials: N
authors.lastname: Besbas
authors.forename: Jörg
authors.initials: J
authors.lastname: Dötsch
authors.forename: Ingo
authors.initials: I
authors.lastname: Franke
authors.forename: Stefan
authors.initials: S
authors.lastname: Fründ
authors.forename: Faysal
authors.initials: F
authors.lastname: Gok
authors.forename: Bernd
authors.initials: B
authors.lastname: Hoppe
authors.forename: Stephanie
authors.initials: S
authors.lastname: Karle
authors.forename: Eberhard
authors.initials: E
authors.lastname: Kuwertz-Bröking
authors.forename: Guido
authors.initials: G
authors.lastname: Laube
authors.forename: Margarita
authors.initials: M
authors.lastname: Neb
authors.forename: Matti
authors.initials: M
authors.lastname: Nuutinen
authors.forename: Fatih
authors.initials: F
authors.lastname: Ozaltin
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rascher
authors.forename: Troels
authors.initials: T
authors.lastname: Ring
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.forename: Joanna A E
authors.initials: JA
authors.lastname: van Wijk
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
mesh_terms: D018118:Chloride Channels / Q000235:genetics; D003402:Creatine Kinase / Q000097:blood; D016368:Frameshift Mutation; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D020125:Mutation, Missense; D009800:Oculocerebrorenal Syndrome / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D021381:Protein Transport / Q000502:physiology; D015499:Renal Tubular Transport, Inborn Errors / Q000097:blood / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: C097539:CLCN6 protein, human; D018118:Chloride Channels; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human