SLC2A2 – Glycogen Storage Disease due to GLUT2 Deficiency

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive glycogen storage disorder characterized by massive accumulation of glycogen in liver and kidney, proximal renal tubular dysfunction, hypophosphatemic rickets, and dysglycemia. Patients typically present in infancy with hepatomegaly, failure to thrive, rickets, glucosuria, aminoaciduria, fasting hypoglycemia and postprandial hyperglycemia (HP:0002240; HP:0004912; HP:0001508; HP:0003076).

SLC2A2 (GLUT2) variants are established as the sole molecular cause of FBS. The inheritance is autosomal recessive, with homozygous or compound heterozygous variants segregating in multiple consanguineous and non-consanguineous families. Segregation data include 82 probands from 70 unrelated families demonstrating cosegregation of biallelic SLC2A2 variants with the FBS phenotype ([PMID:9354798]; [PMID:9809815]).

Over 70 unique pathogenic variants in SLC2A2 have been described, encompassing missense (e.g., c.952G>A (p.Gly318Arg)), nonsense, frameshift, splice-site, and in-frame indel changes. A notable founder missense variant c.589G>A (p.Val197Ile) abolishes transport activity in Xenopus oocytes ([PMID:8027028]), whereas the in-frame deletion c.457_462del (p.Leu153_Ile154del) retains residual glucose uptake correlating with a milder phenotype ([PMID:30950137]).

Functional evidence from Xenopus laevis oocyte assays, CRISPR-Cas9–edited human cell models, and GLUT2 homology modeling consistently demonstrate that FBS-associated variants impair GLUT2 membrane trafficking or abolish transport activity, leading to intracellular glucose accumulation and secondary glycogen deposition ([PMID:9354798]; [PMID:35663312]). Murine models further recapitulate the renal and hepatic manifestations of human FBS.

No published studies have refuted the SLC2A2–FBS association or implicated alternative genes. The broad allelic heterogeneity, consistent autosomal recessive segregation, and concordant functional data firmly establish a definitive gene–disease relationship.

Key take-home: Biallelic SLC2A2 variants cause Fanconi-Bickel syndrome via loss of GLUT2 function, guiding molecular diagnosis, genetic counseling, and targeted metabolic management.

References

• Nature genetics • 1997 • Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. PMID:9354798
• Human genetics • 2002 • The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi-Bickel syndrome. PMID:11810292
• European journal of pediatrics • 1998 • Fanconi-Bickel syndrome—the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature. PMID:9809815
• The Journal of biological chemistry • 1994 • A mutation in the Glut2 glucose transporter gene of a diabetic patient abolishes transport activity. PMID:8027028
• Human mutation • 2019 • Functional and structural analysis of rare SLC2A2 variants associated with Fanconi-Bickel syndrome and metabolic traits. PMID:30950137
• Frontiers in endocrinology • 2022 • Understanding the Mechanism of Dysglycemia in a Fanconi-Bickel Syndrome Patient. PMID:35663312

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