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

Détails

ID Serval
serval:BIB_79FF147750F9
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Fanconi-Bickel syndrome and autosomal recessive proximal tubulopathy with hypercalciuria (ARPTH) are allelic variants caused by GLUT2 mutations.
Périodique
Journal of Clinical Endocrinology and Metabolism
Auteur(s)
Mannstadt M., Magen D., Segawa H., Stanley T., Sharma A., Sasaki S., Bergwitz C., Mounien L., Boepple P., Thorens B., Zelikovic I., Jüppner H.
ISSN
1945-7197 (Electronic)
ISSN-L
0021-972X
Statut éditorial
Publié
Date de publication
2012
Volume
97
Numéro
10
Pages
E1978-E1986
Langue
anglais
Résumé
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.
Mots-clé
Adolescent, Amino Acid Sequence, Animals, 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
Pubmed
Web of science
Open Access
Oui
Création de la notice
15/11/2012 19:41
Dernière modification de la notice
08/05/2019 20:45
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