title: Fanconi-Bickel syndrome and autosomal recessive proximal tubulopathy with hypercalciuria (ARPTH) are allelic variants caused by GLUT2 mutations.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Massachusetts General Hospital, Endocrine Unit, Harvard Medical School, Thier 1051, 55 Fruit Street, Boston Massachusetts 02114, USA. mmannstadt@partners.org
authors.forename: Michael
authors.initials: M
authors.lastname: Mannstadt
authors.forename: Daniella
authors.initials: D
authors.lastname: Magen
authors.forename: Hiroko
authors.initials: H
authors.lastname: Segawa
authors.forename: Takara
authors.initials: T
authors.lastname: Stanley
authors.forename: Amita
authors.initials: A
authors.lastname: Sharma
authors.forename: Shohei
authors.initials: S
authors.lastname: Sasaki
authors.forename: Clemens
authors.initials: C
authors.lastname: Bergwitz
authors.forename: Lourdes
authors.initials: L
authors.lastname: Mounien
authors.forename: Paul
authors.initials: P
authors.lastname: Boepple
authors.forename: Bernhard
authors.initials: B
authors.lastname: Thorens
authors.forename: Israel
authors.initials: I
authors.lastname: Zelikovic
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D053098:Familial Hypophosphatemic Rickets; D005192:Family Health; D005198:Fanconi Syndrome / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D051272:Glucose Transporter Type 1 / Q000235:genetics; D051273:Glucose Transporter Type 2 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics* / Q000378:metabolism; D007015:Hypophosphatemia, Familial / Q000235:genetics* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009865:Oocytes / Q000502:physiology; D010375:Pedigree; D012279:Rickets / Q000235:genetics* / Q000378:metabolism; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics; D014982:Xenopus laevis
chemical_list: D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; C495680:SLC2A2 protein, human; C495678:Slc2a1 protein, mouse; C495682:Slc2a2 protein, mouse; C493555:Slc34a1 protein, mouse; C493563:Slc34a3 protein, mouse; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc