Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent’s DiseaseWu F.a · Reed A.A.C.a · Williams S.E.a · Loh N.Y.a · Lippiat J.D.b, c · Christie P.T.a · Large O.a · Bettinelli A.f · Dillon M.J.d · Goldraich N.P.g · Hoppe B.h · Lhotta K.i · Loirat C.k · Malik R.e · Morel D.l · Kotanko P.j · Roussel B.m · Rubinger D.n · Schrander-Stumpel C.o · Serdaroglu E.p · Nesbit M.A.a · Ashcroft F.b · Thakker R.V.a
aNuffield Department of Clinical Medicine, Academic Endocrine Unit, University of Oxford, and Churchill Hospital, Oxford Centre for Diabetes, Endocrinology and Metabolism, and bDepartment of Physiology, University of Oxford, Oxford, cInstitute of Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds, dDepartment of Nephrology, Great Ormond St Hospital for Children, London, and eAcademic Department of Medicine, Manchester Royal Infirmary, Manchester, UK; fUnité Operative Pediatria, Ospidale Mandic, Merate, Italy; gPediatric Nephrology Unit, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; hDivision of Pediatric Nephrology, Department of Pediatrics, University Hospital Cologne, Cologne, Germany; iAcademic Teaching Hospital Feldkirch, Feldkirch, and jDepartment of Clinical Medicine, Krankenhaus der Barmherzigen Brüder, Graz, Austria; kDepartment of Pediatric Nephrology, Hospital Robert Debre, Paris, lDepartment of Nephrology, Groupe Hospitalier Pellegrin, Bordeaux, and mNephrologie Pediatrique, American Memorial Hospital, Centre Hospitalier Universitaire Reims, Reims, France; nNephrology Department, Hadassah-Hebrew University Medical Centre, Ein-Kerem Campus, Jerusalem, Israel; oDepartment of Clinical Genetics, University Hospital Maastricht and Research Institute for Growth and Development, University of Maastricht, Maastricht, The Netherlands; pDepartment of Pediatric Nephrology, Ege University Medical School, Izmir, Turkey
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Background/Aims: Dent’s disease is caused by mutations in the chloride/proton antiporter, CLC-5, or oculo-cerebro-renal-syndrome-of-Lowe (OCRL1) genes. Methods: Eighteen probands with Dent’s disease were investigated for mutations in CLC-5 and two of its interacting proteins, CLC-4 and cofilin. Wild-type and mutant CLC-5s were assessed in kidney cells. Urinary calcium excretion following an oral calcium challenge was studied in one family. Results: Seven different CLC-5 mutations consisting of two nonsense mutations (Arg347Stop and Arg718Stop), two missense mutations (Ser244Leu and Arg516Trp), one intron 3 donor splice site mutation, one deletion-insertion (nt930delTCinsA) and an in-frame deletion (523delVal) were identified in 8 patients. In the remaining 10 patients, DNA sequence abnormalities were not detected in the coding regions of CLC-4 or cofilin, and were independently excluded for OCRL1. Patients with CLC-5 mutations were phenotypically similar to those without. The donor splice site CLC-5 mutation resulted in exon 3 skipping. Electrophysiology demonstrated that the 523delVal CLC-5 mutation abolished CLC-5-mediated chloride conductance. Sixty percent of women with the CLC-5 deletion-insertion had nephrolithiasis, although calcium excretion before and after oral calcium challenge was similar to that in unaffected females. Conclusions: Three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent’s disease in this patient cohort.
© 2009 S. Karger AG, Basel
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