Fanconi-Bickel syndrome and autosomal recessive proximal tubulopathy with hypercalciuria (ARPTH) are allelic variants caused by GLUT2 mutations

J Clin Endocrinol Metab. 2012 Oct;97(10):E1978-86. doi: 10.1210/jc.2012-1279. Epub 2012 Aug 3.

Abstract

Context: Many inherited disorders of calcium and phosphate homeostasis are unexplained at the molecular level.

Objective: The objective of the study was to identify the molecular basis of phosphate and calcium abnormalities in two unrelated, consanguineous families.

Patients: The affected members in family 1 presented with rickets due to profound urinary phosphate-wasting and hypophosphatemic rickets. In the previously reported family 2, patients presented with proximal renal tubulopathy and hypercalciuria yet normal or only mildly increased urinary phosphate excretion.

Methods: Genome-wide linkage scans and direct nucleotide sequence analyses of candidate genes were performed. Transport of glucose and phosphate by glucose transporter 2 (GLUT2) was assessed using Xenopus oocytes. Renal sodium-phosphate cotransporter 2a and 2c (Npt2a and Npt2c) expressions were evaluated in transgenically rescued Glut2-null mice (tgGlut2-/-).

Results: In both families, genetic mapping and sequence analysis of candidate genes led to the identification of two novel homozygous mutations (IVS4-2A>G and R124S, respectively) in GLUT2, the gene mutated in Fanconi-Bickel syndrome, a rare disease usually characterized by renal tubulopathy, impaired glucose homeostasis, and hepatomegaly. Xenopus oocytes expressing the [R124S]GLUT2 mutant showed a significant reduction in glucose transport, but neither wild-type nor mutant GLUT2 facilitated phosphate import or export; tgGlut2-/- mice demonstrated a profound reduction of Npt2c expression in the proximal renal tubules.

Conclusions: Homozygous mutations in the facilitative glucose transporter GLUT2, which cause Fanconi-Bickel syndrome, can lead to very different clinical and biochemical findings that are not limited to mild proximal renal tubulopathy but can include significant hypercalciuria and highly variable degrees of urinary phosphate-wasting and hypophosphatemia, possibly because of the impaired proximal tubular expression of Npt2c.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Familial Hypophosphatemic Rickets
  • Family Health
  • Fanconi Syndrome / genetics*
  • Fanconi Syndrome / metabolism
  • Female
  • Genes, Recessive / genetics
  • Genetic Variation
  • Genome-Wide Association Study
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 2 / genetics*
  • Glucose Transporter Type 2 / metabolism
  • Humans
  • Hypercalciuria / genetics*
  • Hypercalciuria / metabolism
  • Hypophosphatemia, Familial / genetics*
  • Hypophosphatemia, Familial / metabolism
  • Kidney Tubules, Proximal / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Oocytes / physiology
  • Pedigree
  • Rickets / genetics*
  • Rickets / metabolism
  • Sodium-Phosphate Cotransporter Proteins, Type IIa / genetics
  • Sodium-Phosphate Cotransporter Proteins, Type IIc / genetics
  • Xenopus laevis

Substances

  • Glucose Transporter Type 1
  • Glucose Transporter Type 2
  • SLC2A2 protein, human
  • Slc2a1 protein, mouse
  • Slc2a2 protein, mouse
  • Slc34a1 protein, mouse
  • Slc34a3 protein, mouse
  • Sodium-Phosphate Cotransporter Proteins, Type IIa
  • Sodium-Phosphate Cotransporter Proteins, Type IIc

Supplementary concepts

  • Hypophosphatemic Rickets with Hypercalciuria, Hereditary