HNF1B mutations associate with hypomagnesemia and renal magnesium wasting.
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.
Adalat
Shazia
S
Nephrology Unit, Great Ormond Street Hospital NHS Trust, London WCIN 3JH, UK.
Woolf
Adrian S
AS
Johnstone
Karen A
KA
Wirsing
Andrea
A
Harries
Lorna W
LW
Long
David A
DA
Hennekam
Raoul C
RC
Ledermann
Sarah E
SE
Rees
Lesley
L
van't Hoff
William
W
Marks
Stephen D
SD
Trompeter
Richard S
RS
Tullus
Kjell
K
Winyard
Paul J
PJ
Cansick
Janette
J
Mushtaq
Imran
I
Dhillon
Harjeeta K
HK
Bingham
Coralie
C
Edghill
Emma L
EL
Shroff
Rukshana
R
Stanescu
Horia
H
Ryffel
Gerhart U
GU
Ellard
Sian
S
Bockenhauer
Detlef
D
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*
C496495:HNF1B protein, human; D051539:Hepatocyte Nuclear Factor 1-beta; D008274:Magnesium