SLC2A5 and Hereditary Fructose Intolerance

SLC2A5 encodes the GLUT5 fructose transporter, which was initially hypothesized to play a role in disorders of fructose absorption, including hereditary fructose intolerance. Early studies aimed to determine if mutations in SLC2A5 might underlie clinical presentations of fructose malabsorption, thereby potentially overlapping with hereditary fructose intolerance phenotypes.

Genetic investigations have consistently failed to identify pathogenic coding variants in SLC2A5 among patient cohorts. One study screening eight patients with isolated fructose malabsorption and relevant controls did not reveal mutations in the protein-coding region (PMID:8941659). Similarly, a larger study of 35 individuals with acquired fructose malabsorption documented several gene variants in SLC2A5, but their allele frequencies were comparable to those observed in public databases, and no segregation with disease was observed (PMID:35387598).

Further evaluation of the variant spectrum in SLC2A5 across these studies shows an absence of recurrent or founder variants with clear pathogenic significance. In particular, even when variants such as p.I296V in GLUT5 were tested, they lacked correspondence with changes in the coding sequence and were not accompanied by deleterious alterations at the cDNA level.

Functional assays provide additional context. Experimental assessments, including radiotracer flux studies in oocyte and fibroblast systems, demonstrated that the p.I296V variant in GLUT5 does not impair fructose transport (PMID:28083649). This functional concordance with the normal physiological profile of GLUT5 further diminishes any potential causative link between SLC2A5 and hereditary fructose intolerance.

The lack of both supportive genetic evidence and functional impairment argues strongly against an etiologic role of SLC2A5 variants in hereditary fructose intolerance. There is no evidence of multiple unrelated probands or segregation data that would bolster any suspected association, thereby refuting SLC2A5 as a candidate gene for this condition.

Overall, the comprehensive genetic and experimental data refute a clinically meaningful association between SLC2A5 and hereditary fructose intolerance. Key take‑home sentence: Screening for SLC2A5 variants holds no diagnostic utility in hereditary fructose intolerance, and current evidence does not support its role in the pathophysiology of the disorder.

References

• The Journal of clinical investigation | 1996 | Molecular analysis of the fructose transporter gene (GLUT5) in isolated fructose malabsorption PMID:8941659
• BMC gastroenterology | 2022 | Gene variants of the SLC2A5 gene encoding GLUT5, the major fructose transporter, do not contribute to clinical presentation of acquired fructose malabsorption PMID:35387598
• The Journal of membrane biology | 2017 | Reassessment of GLUT7 and GLUT9 as Putative Fructose and Glucose Transporters PMID:28083649

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