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, Hassen Y. (2009). Compound heterozygous mutations affect protein folding and function in patients with congenital sucrase-isomaltase deficiency. Gastroenterology, 136(3), pp. 883-892. Philadelphia, Pa.: Elsevier 10.1053/j.gastro.2008.11.038

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BACKGROUND & AIMS: Congenital sucrase-isomaltase (SI) deficiency is an autosomal-recessive intestinal disorder characterized by a drastic reduction or absence of sucrase and isomaltase activities. Previous studies have indicated that single mutations underlie individual phenotypes of the disease. We investigated whether compound heterozygous mutations, observed in some patients, have a role in disease pathogenesis. METHODS: We introduced mutations into the SI complementary DNA that resulted in the amino acid substitutions V577G and G1073D (heterozygous mutations found in one group of patients) or C1229Y and F1745C (heterozygous mutations found in another group). The mutant genes were expressed transiently, alone or in combination, in COS cells and the effects were assessed at the protein, structural, and subcellular levels. RESULTS: The mutants SI-V577G, SI-G1073D, and SI-F1745C were misfolded and could not exit the endoplasmic reticulum, whereas SI-C1229Y was transported only to the Golgi apparatus. Co-expression of mutants found on each SI allele in patients did not alter the protein's biosynthetic features or improve its enzymatic activity. Importantly, the mutations C1229Y and F1745C, which lie in the sucrase domains of SI, prevented its targeting to the cell's apical membrane but did not affect protein folding or isomaltase activity. CONCLUSIONS: Compound heterozygosity is a novel pathogenic mechanism of congenital SI deficiency. The effects of mutations in the sucrase domain of SIC1229Y and SIF1745C indicate the importance of a direct interaction between isomaltase and sucrose and the role of sucrose as an intermolecular chaperone in the intracellular transport of SI.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics

UniBE Contributor:

Leeb, Tosso

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 590 Animals (Zoology)
600 Technology > 610 Medicine & health
600 Technology > 630 Agriculture

ISSN:

0016-5085

Publisher:

Elsevier

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:25

Last Modified:

13 Aug 2015 08:46

Publisher DOI:

10.1053/j.gastro.2008.11.038

PubMed ID:

19121318

Web of Science ID:

000263751400027

BORIS DOI:

10.7892/boris.38288

URI:

https://boris.unibe.ch/id/eprint/38288 (FactScience: 220926)

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