Severe pathogenic variants of intestinal sucrase-isomaltase interact avidly with the wild type enzyme and negatively impact its function and trafficking

Biochim Biophys Acta Mol Basis Dis. 2022 Nov 1;1868(11):166523. doi: 10.1016/j.bbadis.2022.166523

PMID: 35985447

Diab M Husein, Sandra Rizk, Abdullah Hoter

Highlights: This study provides novel insights into the potential role of heterozygosity in the pathophysiology of congenital sucrase-isomaltase deficiency and irritable bowel syndrome.

Abstract

Background: The main disaccharidase of the small intestine, sucrose-isomaltase (SI), has a varied α-glucosidase activity profile. The emergence of sucrose and starch maldigestion in people with mutations in the SI gene, such as in congenital sucrase-isomaltase deficiency (CSID), is a manifestation of the significance of SI in gut health. Defective SI gene variations (SIGVs), both common and rare, have been demonstrated to increase the incidence of IBS, a condition with symptoms and clinical characteristics comparable to CSID, among symptomatic heterozygote carriers as well.

Objective and results: Here, the effects of the most prevalent and highly pathogenic SIGVs on wild type SI (SIWT) are examined by modifying an in vitro system that mimics the heterozygosity of the SI gene. The findings show that pathogenic SI mutations actively engage with SIWT, disrupt the heterodimer's trafficking behavior, alter the biosynthetic pattern, and negatively affect its enzymatic function. The ability of SIGVs to behave in a semi-dominant manner by sequestering the SIWT copy into an inactive form of the enzyme heterodimer is demonstrated by the in vitro recapitulation of a heterozygous state.

Conclusion: New information about the probable function of heterozygosity in the pathophysiology of CSID and IBS is provided by this study.

Keywords: Congenital sucrase-isomaltase deficiency (CSID), Enzyme function, Heterodimeric interactions, Irritable bowel syndrome (IBS), Protein trafficking, SI gene variants (SIGVs), Sucrase-isomaltase (SI)