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Table of Contents
Vol. 112, No. 2, 2009
Issue release date: May 2009
Section title: Original Paper
Nephron Physiol 2009;112:p27–p36
(DOI:10.1159/000213506)

OCRL1 Mutations in Dent 2 Patients Suggest a Mechanism for Phenotypic Variability

Shrimpton A.E.a · Hoopes, Jr. R.R.b · Knohl S.J.b · Hueber P.b · Reed A.A.C.c · Christie P.T.c · Igarashi T.d · Lee P.e · Lehman A.f · White C.f · Milford D.V.g · Sanchez M.R.h · Unwin R.i · Wrong O.M.i · Thakker R.V.c · Scheinman S.J.b
Departments of aPathology and bMedicine, SUNY Upstate Medical University, Syracuse, N.Y., USA; cNuffield Department of Medicine, University of Oxford, Oxford, UK; dDepartment of Pediatrics, University of Tokyo, Tokyo, Japan; eCharles Dent Metabolic Unit, The National Hospital for Neurology and Neurosurgery, London, UK; fDepartment of Pediatrics, BC Children’s Hospital, Vancouver, BC., Canada; gDepartment of Nephrology, Birmingham Children’s Hospital, Birmingham, UK; hNephrology Unit, Hospital Puerta del Mar, Cadiz, Spain; iDepartment of Medicine, Royal Free and University College Medical School, London, UK

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: October 14, 2008
Accepted: December 30, 2008
Published online: April 18, 2009
Issue release date: May 2009

Number of Print Pages: 1
Number of Figures: 1
Number of Tables: 2

ISSN: (Print)
eISSN: 1660-2137 (Online)

For additional information: http://www.karger.com/NEP

Abstract

Background/Aims: 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.

© 2009 S. Karger AG, Basel


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: October 14, 2008
Accepted: December 30, 2008
Published online: April 18, 2009
Issue release date: May 2009

Number of Print Pages: 1
Number of Figures: 1
Number of Tables: 2

ISSN: (Print)
eISSN: 1660-2137 (Online)

For additional information: http://www.karger.com/NEP


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