title: HNF1B mutations associate with hypomagnesemia and renal magnesium wasting.
abstract: 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 Mg(2+), thus describing a role for HNF1B not only in nephrogenesis but also in the maintenance of tubular function.
authors.affiliation: Nephrology Unit, Great Ormond Street Hospital NHS Trust, London WCIN 3JH, UK.
authors.forename: Shazia
authors.initials: S
authors.lastname: Adalat
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
authors.forename: Karen A
authors.initials: KA
authors.lastname: Johnstone
authors.forename: Andrea
authors.initials: A
authors.lastname: Wirsing
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
authors.forename: David A
authors.initials: DA
authors.lastname: Long
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Ledermann
authors.forename: Lesley
authors.initials: L
authors.lastname: Rees
authors.forename: William
authors.initials: W
authors.lastname: van't Hoff
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Marks
authors.forename: Richard S
authors.initials: RS
authors.lastname: Trompeter
authors.forename: Kjell
authors.initials: K
authors.lastname: Tullus
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Winyard
authors.forename: Janette
authors.initials: J
authors.lastname: Cansick
authors.forename: Imran
authors.initials: I
authors.lastname: Mushtaq
authors.forename: Harjeeta K
authors.initials: HK
authors.lastname: Dhillon
authors.forename: Coralie
authors.initials: C
authors.lastname: Bingham
authors.forename: Emma L
authors.initials: EL
authors.lastname: Edghill
authors.forename: Rukshana
authors.initials: R
authors.lastname: Shroff
authors.forename: Horia
authors.initials: H
authors.lastname: Stanescu
authors.forename: Gerhart U
authors.initials: GU
authors.lastname: Ryffel
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
mesh_terms: D000293:Adolescent; D005190:Family; D005260:Female; D006580:Genetic Carrier Screening; D005919:Glomerular Filtration Rate; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000002:abnormalities* / Q000033:anatomy & histology / Q000000981:diagnostic imaging; D008274:Magnesium / Q000097:blood / Q000652:urine; D008275:Magnesium Deficiency / Q000235:genetics*; D008297:Male; D009154:Mutation; D012189:Retrospective Studies; D014463:Ultrasonography; D019282:Wasting Syndrome / Q000235:genetics*
chemical_list: C496495:HNF1B protein, human; D051539:Hepatocyte Nuclear Factor 1-beta; D008274:Magnesium