Congenital sucrase-isomaltase deficiency arising from cleavage and secretion of a mutant form of the enzyme

Jacob, Ralf; Zimmer, Klaus–Peter; Schmitz, J; Naim, Hassan Y.

doi:10.1172/jci9677

Cited by 48 publications

(37 citation statements)

References 32 publications

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“…Identification of an Amino Acid Substitution C635R and Assessment of Its Function-Previous reports have shown that point mutations in the coding region of the SI gene are responsible for misfolding and alteration in the trafficking of SI along the secretory pathway (5,6,16,23,24). We therefore isolated the cDNA encoding SI from the biopsy specimen of the patient and analyzed its sequence in comparison to the wild type cDNA.…”

Section: Table 1 Comparison Of An Amino Acid Stretch Encompassing Thementioning

confidence: 99%

Altered Folding, Turnover, and Polarized Sorting Act in Concert to Define a Novel Pathomechanism of Congenital Sucrase-Isomaltase Deficiency

Keiser¹,

Alfalah²,

Pröpsting³

et al. 2006

Journal of Biological Chemistry

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Naturally occurring mutants of membrane and secretory proteins are often associated with the pathogenesis of human diseases. Here, we describe the molecular basis of a novel phenotype of congenital sucrase-isomaltase deficiency (CSID), a disaccharide malabsorption disorder of the human intestine in which several structural features and functional capacities of the brush-border enzyme complex sucrase-isomaltase (SI) are affected. The cDNA encoding SI from a patient with CSID reveals a mutation in the isomaltase subunit of SI that results in the substitution of a cysteine by an arginine at amino acid residue 635 (C635R). When this mutation is introduced into the wild type cDNA of SI a mutant enzyme, SI C635R , is generated that shows a predominant localization in the endoplasmic reticulum. Nevertheless, a definite localization of SI C635R in the Golgi apparatus and at the cell surface could be also observed. Epitope mapping with conformation-specific mAbs protease sensitivity assays, and enzymatic activity measurements demonstrate an altered folding pattern of SI C635R that is responsible for a substantially increased turnover rate and an aberrant sorting profile. Thus, SI C635R becomes distributed also at the basolateral membrane in contrast to wild type SI. Concomitant with the altered sorting pattern, the partial detergent extractability of wild type SI shifts to a complete detergent solubility with Triton X-100. The mutation has therefore affected an epitope responsible for the apical targeting fidelity of SI. Altogether, the combined effects of the C635R mutation on the turnover rate, function, polarized sorting, and detergent solubility of SI constitute a unique and novel pathomechanism of CSID.The utilization of misfolding-related diseases has proven to be invaluable in dissection of the molecular mechanisms of protein transport and has unraveled several intriguing cell biological phenomena, such as in cases of congenital sucrase-isomaltase deficiency (CSID).3 This intestinal autosomal recessive disorder is characterized by the absence of the sucrase and most of the maltase digestive activity within the sucraseisomaltase (SI) enzyme complex. The isomaltase activity varies from absent to normal (1). Clinically, the disease is manifested as an osmoticfermentative diarrhea upon ingestion of disaccharides and oligosaccharides (2). Analysis of this disorder at the molecular and subcellular levels has unraveled a number of phenotypes of CSID, which are characterized by perturbations in the intracellular transport, polarized sorting, aberrant processing, and defective function of SI (3-5). A few examples have been also reported, in which the misfolded protein products may escape the quality control system, instead of being either degraded or retained in the ER. A mutation at the position 620 of SI (L620P), for example, has been identified as one of the possible genetic modifications occurring in the CSID (6). Although this mutant is mainly found to be localized in the ER, it can be at least partially expressed als...

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Section: Table 1 Comparison Of An Amino Acid Stretch Encompassing Thementioning

confidence: 99%

Altered Folding, Turnover, and Polarized Sorting Act in Concert to Define a Novel Pathomechanism of Congenital Sucrase-Isomaltase Deficiency

Keiser¹,

Alfalah²,

Pröpsting³

et al. 2006

Journal of Biological Chemistry

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“…In some cases, maltase glucoamylase activity was also decreased. Several phenotypes generated by different point mutations and even in the coding region of the SI protein have been described (2,6,8,9).…”

Section: Discussionmentioning

confidence: 99%

Mosaic Pattern of Sucrase Isomaltase Deficiency in Two Brothers

et al. 2008

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ABSTRACT:The pathophysiology of mucosal changes observed in infants with chronic protracted diarrhea is poorly understood. We report on two brothers suffering from a special form of sucrase isomaltase (SI) deficiency. The children presented with weight loss and dyspepsia after sucrose exposition. We performed an H 2 respiration test, which showed a pathologic result in the younger brother. Analysis of the brush border enzyme activities showed low expression of lactase and SI. Immunoelectron microscopy of duodenal biopsies showed an isolated SI deficiency in a mosaic pattern [e.g., 42% (14%) crypt enterocytes and 64% (59%) villus enterocytes with decreased amounts of SI on microvilli], whereas lactase and aminopeptidase n (ApN) were present at the apical membrane of all cells in a normal range. The SI mosaic pattern of these patients shows that the enterocytes contain low amounts of SI on the apical membrane but express normal quantities of other disaccharidases. These findings suggest the existence of different clonal expressions or specific (posttranslational) mechanisms of postGolgi transportation for individual brush border enzymes. It remains unresolved whether the mosaic distribution is part of a normal maturation process or caused by a lack of an overall control mechanism in the expression of brush border hydrolases. (Pediatr Res 63: 79-83, 2008)

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“…Studies on the sucrase-isomaltase protein in individuals of European extraction suggest that various different mutations cause the deficiency, and so far three exonic mutations have been identified. One results in substitution of proline by a glutamine at amino acid 1098 (Ouwendijk et al 1998) and one causes the protein to be secreted (Jacob et al 2000), and one glutamine by arginine 117 affects apical protein transport (Spodsberg et al 2001). It is not known whether any one mutation occurs at higher frequency.…”

Section: Sucrase-isomaltase Deficiencymentioning

confidence: 99%

Genetic influences on carbohydrate digestion

Swallow¹

2003

NRR

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The diversity of the human genome leads to many functional differences between individuals. The present review focuses on genetic variations, both rare and common, that are of relevance to digestion of the sugars and starches that form a major part of human diets, and considers these in relation to the evolution of our species. For example, intolerances of dietary saccharides are not usually life-threatening because symptoms can be avoided by removal of the offending sugar from the diet, and deficiencies of the relevant enzymes are in some cases found at relatively high frequencies in certain populations. This is of evolutionary interest in relation to changes in the human diet, and the lactase-persistence polymorphism, in particular, provides an interesting model. More of the world's adult population are lactase-deficient than have high lactase. The other deficiencies are however much more rare, but the significance of variant alleles at these loci, and also heterozygosity for deficiency alleles, to human nutrition and health is an area that is relatively unexplored.

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Congenital sucrase-isomaltase deficiency arising from cleavage and secretion of a mutant form of the enzyme

Cited by 48 publications

References 32 publications

Altered Folding, Turnover, and Polarized Sorting Act in Concert to Define a Novel Pathomechanism of Congenital Sucrase-Isomaltase Deficiency

Altered Folding, Turnover, and Polarized Sorting Act in Concert to Define a Novel Pathomechanism of Congenital Sucrase-Isomaltase Deficiency

Mosaic Pattern of Sucrase Isomaltase Deficiency in Two Brothers

Genetic influences on carbohydrate digestion

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