{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSucrase‐isomaltase (SI) is a critical brush border enzyme responsible for hydrolyzing sucrose and digesting a major fraction of dietary starch, ensuring proper carbohydrate absorption. Aberrations in the SI gene lead to markedly reduced or absent disaccharidase activity, resulting in congenital sucrase‐isomaltase deficiency (CSID) and can contribute to irritable bowel syndrome–like symptoms. In patients with CSID, both homozygous and heterozygous mutations have been identified that disrupt the normal function of SI, thereby impairing the breakdown of dietary sugars and leading to chronic diarrhea and abdominal discomfort. Furthermore, such variants may also modify disease susceptibility in broader gastrointestinal conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe expression and functionality of SI are tightly regulated at multiple levels. During enterocyte differentiation, posttranslational modifications such as glycosylation play an essential role in ensuring the accurate cell surface targeting and maturation of SI, while transcription factors—particularly HNF‐1α and HNF‐1β—are crucial for driving SI gene expression in response to varying glucose levels. Additionally, inhibitors like L‐arabinose modulate SI activity by transiently interfering with its enzyme–substrate interactions, and molecular chaperones such as GRP94 contribute to the proper folding and quality control of SI in the endoplasmic reticulum."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in SI not only compromise its catalytic activity but also affect its folding, trafficking, and stability. Specific mutations have been shown to induce misfolding that leads to aberrant retention of SI in the endoplasmic reticulum–Golgi intermediate compartments or promote an increased turnover rate, culminating in reduced enzyme levels at the apical membrane. Moreover, in contexts beyond typical gastrointestinal malabsorption, SI mutations have been implicated in altered metabolic profiles, as observed in certain cancer types, highlighting its broader importance in cellular metabolism and homeostasis. Genotype–phenotype studies further underscore the significance of precise SI processing for maintaining intestinal integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marwan Alfalah, Markus Keiser, Tosso Leeb, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Compound heterozygous mutations affect protein folding and function in patients with congenital sucrase-isomaltase deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2008.11.038"}], "href": "https://doi.org/10.1053/j.gastro.2008.11.038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19121318"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19121318"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Koldo Garcia-Etxebarria, Tenghao Zheng, Ferdinando Bonfiglio, et al. 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