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HNF1B Mutations Associate with Hypomagnesemia and Renal Magnesium Wasting

Shazia Adalat^*, Adrian S. Woolf^*, Karen A. Johnstone, Andrea Wirsing, Lorna W. Harries, David A. Long^*, Raoul C. Hennekam^*, Sarah E. Ledermann^*, Lesley Rees^*, William van't Hoff^*, Stephen D. Marks^*, Richard S. Trompeter^*, Kjell Tullus^*, Paul J. Winyard^*, Janette Cansick^*, Imran Mushtaq^*, Harjeeta K. Dhillon^*, Coralie Bingham, Emma L. Edghill, Rukshana Shroff^*, Horia Stanescu, Gerhart U. Ryffel, Sian Ellard and Detlef Bockenhauer^*

^* Nephrology, Urology, and Clinical Genetics Units, Great Ormond Street Hospital NHS Trust, and Centre for Nephrology, Royal Free Hospital, University College London, London, and Peninsula Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom; and Institut für Zellbiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany

Correspondence: Dr. Detlef Bockenhauer, Great Ormond Street Hospital NHS Trust, London WCIN 3JH, UK. Phone: 44-20 74059200; Fax: 44-20 78298841 E-mail: detlef.bockenhauer{at}NHS.net

Received for publication June 24, 2008. Accepted for publication January 5, 2009.

Mutations in hepatocyte nuclear factor 1B (HNF1B), which is a transcription factor expressed in tissues including renal epithelia, associate with abnormal renal development. While studying renal phenotypes of children with HNF1B mutations, we identified a teenager who presented with tetany and hypomagnesemia. We retrospectively reviewed radiographic and laboratory data for all patients from a single center who had been screened for an HNF1B mutation. We found heterozygous mutations in 21 (23%) of 91 cases of renal malformation. All mutation carriers had abnormal fetal renal ultrasonography. Plasma magnesium levels were available for 66 patients with chronic kidney disease (stages 1 to 3). Striking, 44% (eight of 18) of mutation carriers had hypomagnesemia (<1.58 mg/dl) compared with 2% (one of 48) of those without mutations (P < 0.0001). The median plasma magnesium was significantly lower among mutation carriers than those without mutations (1.68 versus 2.02 mg/dl; P < 0.0001). Because hypermagnesuria and hypocalciuria accompanied the hypomagnesemia, we analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. These results extend the phenotype of HNF1B mutations to include hypomagnesemia. HNF1B regulates transcription of FXYD2, which participates in the tubular handling of Mg²⁺, thus describing a role for HNF1B not only in nephrogenesis but also in the maintenance of tubular function.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673