title: OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability.
abstract: OBJECTIVE
  Dent disease is an X-linked renal proximal tubulopathy associated with mutations in CLCN5 (Dent 1) or OCRL1 (Dent 2). OCRL1 mutations also cause the oculocerebrorenal syndrome of Lowe.
  
  
  METHODS
  Dent patients with normal sequence for CLCN5 were sequenced for mutations in OCRL1. By analyzing these and all other OCRL1 mutations reported, a model relating OCRL1 mutations to the resulting disease (Dent 2 or Lowe's) was developed.
  
  
  RESULTS
  Six boys with Dent disease had novel OCRL1 mutations: two missense (R301H, G304E) and four mutations predicted to produce premature termination codons (L56DfsX1, S149X, P161PfsX3, and M170IfsX1). These include one of the original patients reported by Dent and Friedman. Slit lamp examinations revealed early cataracts in only one boy with normal vision. None of these Dent 2 patients had metabolic acidosis; 3 had mild mental retardation. Analysis of all known OCRL1 mutations show that Dent 2 mutations fall into two classes that do not overlap with Lowe mutations. Bioinformatics analyses identified expressed OCRL1 splice variants that help explain the variability of those clinical features that distinguish Dent disease from Lowe syndrome.
  
  
  CONCLUSIONS
  OCRL1 mutations can cause the renal phenotype of Dent disease, without acidosis or the dramatic eye abnormalities typical of Lowe syndrome. We propose a model to explain the phenotypic variability between Dent 2 and Lowe's based on distinctly different classes of mutations in OCRL1 producing splice variants.
authors.affiliation: Department of Pathology, SUNY Upstate Medical University, Syracuse, N.Y. 13346, USA.
authors.forename: Antony E
authors.initials: AE
authors.lastname: Shrimpton
authors.forename: Richard R
authors.initials: RR
authors.lastname: Hoopes
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Knohl
authors.forename: Paul
authors.initials: P
authors.lastname: Hueber
authors.forename: Anita A C
authors.initials: AA
authors.lastname: Reed
authors.forename: Paul T
authors.initials: PT
authors.lastname: Christie
authors.forename: Takashi
authors.initials: T
authors.lastname: Igarashi
authors.forename: Philip
authors.initials: P
authors.lastname: Lee
authors.forename: Anna
authors.initials: A
authors.lastname: Lehman
authors.forename: Colin
authors.initials: C
authors.lastname: White
authors.forename: David V
authors.initials: DV
authors.lastname: Milford
authors.forename: Manuel Rivero
authors.initials: MR
authors.lastname: Sanchez
authors.forename: Robert
authors.initials: R
authors.lastname: Unwin
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Wrong
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Scheinman
mesh_terms: D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics; D018389:Codon, Nonsense; D019295:Computational Biology; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense; D009800:Oculocerebrorenal Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms; D015499:Renal Tubular Transport, Inborn Errors / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels; D018389:Codon, Nonsense; D020033:Protein Isoforms; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human