Dataset Information

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

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.

SUBMITTER: Mannstadt M

PROVIDER: S-EPMC3462928 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Since the intronic mutation in SLC2A2 did not influence the activity of GLUT2, we undertook more investigation to understand the underlying molecular mechanisms of dysglycemia in FBS. We ran Nanostring miRNA panel v3b covering ~800 miRNAs in the patient, mother, and aged- and gender-matching healthy controls with no family history of dysglycemia. We noticed a higher degree of correlation between the patient and the gender and age-matched healthy control, rather than between the patient and the mother, suggesting that the miRNA expression profile might be more influenced by the age and gender rather than relatedness (Supplementary Fig. S5). The unsupervised hierarchical clustering revealed 123 miRs expressed specifically in the patient sample (Supplementary Table S2). The function of these miRNAs was interrogated by using Ingenuity Pathway (IPA) analysis software which returned 118 mapped miRs (Fig. 10). Here we report 30 miRNAs with the highest number of counts difference in the patient in comparison to controls (Fig. 11). We found that 14 of them were correlated with T1DM: 10 miRNAs (miR-199a, miR-25-3p, miR-93-5p, miR-19b-3p, miR-107, miR-24-3p. miR-18a-5p, miR-125b-5p, miR-324-5p, miR-331-3p, and hsa-miR-143-3p) were overexpressed in the control as compared to the patient, and 3 miRNAs (miR-144-3p , let-7e-5p, hsa-miR-29a-3p) were significantly overexpressed in the patient in comparison to the control. Molecular networks, including molecules inferred from previous studies, were generated by IPA functional analysis software (Supplementary Fig. S6). The molecular networks were given a score based on the number of molecules represented in the study dataset as compared to the literature. Network 1 (score 33) includes the genes and miRNAs implicated in organismal injury and abnormalities, skeletal and muscular system development and function, and tissue morphology. The miR-144 family integrated into the network 1. Network 2 (score 31) includes insulin and other genes and miRNAs implicated in glomerular injury, inflammatory disease, inflammatory response, and included miR-29 and let-7 families. These results suggest that dysglycemia in the patient with intronic mutation might be associated with the deregulation of miRNAs involved in insulin production and secretion in beta cells.