Potential association between irritable bowel syndrome and the gene encoding human intestinal sucrase‐isomaltase (LB131)

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Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal pain and alterations in bowel pattern with a prevalence of 10‐15 % in humans. The molecular basis of IBS is not well understood. We sequenced the coding region of the sucrase‐isomaltase gene (SI) in a mother and her two children who suffer from IBS. The only polymorphism we found to be homozygous or heterozygous was Val15Phe (V15F, rs9290264, g.7526G>T, c.43G>T). We assessed the role of this exchange at the biochemical, cellular and functional levels by expressing SI containing V15F (SI‐V15F) in COS‐1 cells. The biosynthesis, glycosylation and folding of SI‐V15F were essentially comparable to those in wild type SI. The substitution of Val in the first α‐helix of the transmembrane domain of SI by a bulky Phe may have implications on the mode of association of SI with the inner leaflet of the membrane. For this, we investigated the association of SI‐V15F with lipid rafts by assessment of its solubility towards the non‐ionic detergent Triton X‐100 (TX‐100). In comparison to wild type SI, SI‐V15F is more soluble in TX‐100, i.e. less associated with lipid rafts. Cell surface biotinylation indicated that the trafficking of SI‐V15F to the plasma membrane is reduced by almost 20 % as compared to wild type SI. Finally, SI‐V15F revealed a 35 % decreased sucrase activity. Altogether, the combinatorial effects of reduced cell surface expression and enzymatic activity levels lead to a substantial decrease in the overall digestion capacity of SI‐V15F and strongly suggest an association between IBS and the substitution V15F.

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