Compound Heterozygous Mutations Affect Protein Folding and Function in Patients With Congenital Sucrase-Isomaltase Deficiency

Alfalah, Marwan; Keiser, Markus; Leeb, Tosso; Zimmer, Klaus–Peter; Naim, Hassan Y.

doi:10.1053/j.gastro.2008.11.038

Cited by 61 publications

(64 citation statements)

References 29 publications

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“…Together with the immediate effects of Miglustat on the disaccharidase function (Amiri and Naim 2012), the mildness or severity of carbohydrate malabsorption elicited by Miglustat depends on whether the patients under Miglustat treatment are heterozygous for mutations in the SI or LPH genes or are lactose-intolerant. In fact, regarding the SI gene, 13 % of the American population is heterozygous for the mutation Gly1073Asp, 9 % for the mutation Phe1745Cys and 6 % for Val577Gly (Sander et al 2006;Alfalah et al 2009;Uhrich et al 2012). All three mutations generate a malfolded, enzymatically inactive and transport-incompetent SI protein.…”

Section: Discussionmentioning

confidence: 99%

Long term differential consequences of miglustat therapy on intestinal disaccharidases

Amiri¹,

Naim²

2014

J of Inher Metab Disea

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Miglustat is an oral medication for treatment of lysosomal storage diseases such as Gaucher disease type I and Niemann Pick disease type C. In many cases application of Miglustat is associated with symptoms similar to those observed in intestinal carbohydrate malabsorption. Previously, we have demonstrated that intestinal disaccharidases are inhibited immediately by Miglustat in the intestinal lumen. Nevertheless, the multiple functions of Miglustat hypothesize long term effects of Miglustat on intracellular mechanisms, including glycosylation, maturation and trafficking of the intestinal disaccharidases. Our data show that a major long term effect of Miglustat is its interference with N-glycosylation of the proteins in the ER leading to a delay in the trafficking of sucrase-isomaltase. Also association with lipid rafts and plausibly apical targeting of this protein is partly affected in the presence of Miglustat. More drastic is the effect of Miglustat on lactase-phlorizin hydrolase which is partially blocked intracellularly. The de novo synthesized SI and LPH in the presence of Miglustat show reduced functional efficiencies according to altered posttranslational processing of these proteins. However, at physiological concentrations of Miglustat (≤50 μM) a major part of the activity of these disaccharidases is found to be still preserved, which puts the charge of the observed carbohydrate maldigestion mostly on the direct inhibition of disaccharidases in the intestinal lumen by Miglustat as the immediate side effect.

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Section: Discussionmentioning

confidence: 99%

Long term differential consequences of miglustat therapy on intestinal disaccharidases

Amiri¹,

Naim²

2014

J of Inher Metab Disea

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“…An increase in the enzymatic activity of intestinal lactase-phlorizin hydrolase, for example, has been attributed to the presence of O-linked glycans (Naim and Lentze, 1992), which reveal substantial structural alterations during cellular differentiation and the elicited changes in the expression profiles of several glucosyltransferases (Weiser, 1973). One hypothesis suggests that the SI activity correlates with the expression of one healthy allele or two healthy alleles of the SI gene (Alfalah et al, 2009). SI, the most abundant protein in the intestinal brush border membrane, is a type II integral membrane protein responsible for the terminal digestion of dietary sucrose and starch.…”

Section: Introductionmentioning

confidence: 99%

Impact of glycosylation and detergent-resistant membranes on the function of intestinal sucrase-isomaltase

Wetzel¹,

Heisenberg²,

Rohwedder³

et al. 2009

BCHM

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Sucrase-isomaltase (SI) is a highly N- and O-glycosylated intestinal brush border membrane protein. SI is sorted with high fidelity to the apical membrane via O-linked glycans that mediate its association with lipid rafts or detergent-resistant membranes (DRMs). Here, we show that N- and O-glycosylation and DRMs are implicated in the regulation of the function of SI in intestinal Caco-2 cells. The activities of sucrase (SUC) and isomaltase (IM) increase substantially in DRMs when N- and O-glycosylation patterns are intact. Disruption of DRMs by solubilization with Triton X-100 at 37 degrees C substantially reduces the activities of SUC and IM. Furthermore, modulation of O-glycosylation by benzyl-2-acetamido-2-deoxy-alpha-d-galactopyranoside and N-glycosylation by deoxymannojirimycin is linked to a decreased capacity of SI to associate with DRMs, with a subsequent reduction of the enzymatic activities of SUC and IM. This is the first report that reveals a direct role of N- and O-glycans in association with DRMs in regulating the function of a membrane glycoprotein.

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“…The effects were assessed at the protein and subcellular levels. An earlier evaluation conducted in a similar fashion had shown that the previously described compound heterozygote mutations on exons 16 and 27 blocked the SI trafficking from the endoplasmic reticulum to the Golgi apparatus (5). Similarly, analysis of the novel compound heterozygote mutation resulted in delayed trafficking of SI from the endoplasmic reticulum, suggesting an implication of this SI variant in the onset of CSID.…”

Section: Resultsmentioning

confidence: 88%

“…One of these methods is the 13 C-based breath test, the results of which have been found to correlate well with duodenal mucosal enzyme analysis (4). Another approach is SI exome genetic sequencing, which has identified both homozygous mutations and compound heterozygote mutations that cause CSID (5–7). …”

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confidence: 99%

Congenital Sucrase‐Isomaltase Deficiency

Chumpitazi

Robayo–Torres

Opekun

et al. 2012

J. pediatr. gastroenterol. nutr.

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Compound Heterozygous Mutations Affect Protein Folding and Function in Patients With Congenital Sucrase-Isomaltase Deficiency

Cited by 61 publications

References 29 publications

Long term differential consequences of miglustat therapy on intestinal disaccharidases

Long term differential consequences of miglustat therapy on intestinal disaccharidases

Impact of glycosylation and detergent-resistant membranes on the function of intestinal sucrase-isomaltase

Congenital Sucrase‐Isomaltase Deficiency

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