Novel OCRL mutations in patients with Dent-2 disease

Article type: Research Article

Authors: Böckenhauer, Detlef | Bökenkamp, Arend | Nuutinen, Matti | Unwin, Robert | van't Hoff, William | Sirimanna, Tony | Vrljicak, Kristina | Ludwig, Michael^;

Affiliations: Department of Nephrology, Great Ormond Hospital for Children, London, UK | Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands | Department of Pediatrics and Adolescence, Oulu University Hospital, Oulu, Finland | UCL Centre for Nephrology, Royal Free Hospital and Campus, University College Medical School, London, UK | Department of Audiology, Great Ormond Hospital for Children, London, UK | Department of Nephrology, University Children' Hospital, Zagreb, Croatia | Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany

Note: [] Corresponding author: Michael Ludwig, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Tel.: +49 228 6885 418; Fax:+49 228 6885 401; E-mail: [email protected].

Abstract: Dent disease is an X-linked tubulopathy frequently caused by mutations in the CLCN5 gene encoding the voltage-gated chloride channel and chloride/proton antiporter, ClC-5. About 15% of patients with a Dent' phenotype have mutations in the OCRL gene, which also causes Lowe oculocerebrorenal syndrome. To distinguish these patients from the more severe Lowe phenotype, they are diagnosed as having Dent-2 disease. We studied 14 CLCN5-negative patients from 12 families with a phenotype resembling Dent disease for defects in OCRL. In six of these kindreds three novel (c.149+1G>A, c.1126A>T, c.1547T>C) and three repeatedly observed mutations (c.166_167delTT, c.901C>T, c.1426C>T) were discovered. With the exception of a lower prevalence of nephrocalcinosis, the renal phenotype is identical with patients harboring a CLCN5 mutation. Affected children may have some of the extra-renal symptoms of Lowe syndrome, such as peripheral cataracts, mental impairment, stunted growth or elevation of creatine kinase/lactate dehydrogenase, blurring the distinction between those two clinical entities.

Keywords: Dent-2 disease, OCRL gene, proximal tubulopathy, cataracts, mental retardation

DOI: 10.3233/PGE-2012-005

Journal: Journal of Pediatric Genetics, vol. 1, no. 1, pp. 15-23, 2012