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Molecular basis for glucose-galactose malabsorption
Ernest M Wright1, Eric Turk, Martin G Martin
1Department of Physiology, UCLA School of Medicine, Los Angeles, CA 90095-1751, USA. ewright@mednet.ucla.edu
Insights
Mutations in the sodium-glucose cotransporter 1 (SGLT1) gene cause glucose-galactose malabsorption (GGM) in infants. These genetic defects impair sugar transport by producing nonfunctional or improperly targeted SGLT1 proteins.
Area of Science:
- Genetics
- Molecular Biology
- Gastroenterology
Background:
- Glucose-galactose malabsorption (GGM) is a severe, life-threatening inherited disorder in newborns.
- GGM symptoms include severe diarrhea triggered by dietary sugars like lactose, glucose, and galactose.
Purpose of the Study:
- To investigate if mutations in the sodium-glucose cotransporter 1 (SGLT1) gene are the cause of GGM.
- To identify and characterize mutations in the SGLT1 gene in GGM patients.
Main Methods:
- Isolated human SGLT1 cDNA (hSGLT1) and mapped the gene to chromosome 22q13.1.
- Screened 46 GGM patients for SGLT1 mutations, identifying various types including missense, nonsense, and frameshift.
- Utilized the Xenopus laevis oocyte expression system to assess the functional impact of identified mutations on sugar transport.
Main Results:
- Identified causative mutations in the SGLT1 gene in all 46 GGM patients studied.
- Nonsense, frameshift, and splice site mutations resulted in truncated, nonfunctional SGLT1 proteins.
- Most missense mutations led to stable but mis-trafficked SGLT1 proteins that did not reach the plasma membrane; one mutant showed impaired sugar transport despite membrane localization.
Conclusions:
- Mutations in the SGLT1 gene are definitively the cause of glucose-galactose malabsorption.
- Impaired sugar transport in GGM is primarily due to truncated SGLT1 proteins or defects in their trafficking to the cell membrane.
Abstract:
Glucose-galactose malabsorption (GGM) is an autosomal recessive disease that presents in newborn infants as a life-threatening diarrhea. The diarrhea ceases within 1 h of removing oral intake of lactose, glucose, and galactose, but promptly returns with the introduction of one or more of the offending sugars into the diet. Our goal is to determine whether or not mutations in the sodium-glucose cotransporter gene (SGLT1) are responsible for GGM. We first isolated the human cDNA (hSGLT1), mapped the gene, and identified its chromosomal location (22q13.1). Our approach was then to screen GGM patients for mutations in hSGLT1 and then determine if these caused defects in sugar transport using the Xenopus laevis oocyte expression system. In 46 patients we have identified the mutations responsible for GGM. These included missense, nonsense, frame shift, splice site, and promoter mutations. In 30 patients, the same mutations were on both alleles, and the remaining 16 had different mutations on each allele (compound heterozygotes). Several mutations (e.g., C355S) were found in unrelated patients. The nonsense, frame shift, and splice site mutations all produce nonfunctional truncated proteins. In 22 out of the 23 missense mutations tested in the oocyte expression system, the proteins were translated and were stable in the cell, but did not reach the plasma membrane. In four of these mutants, an alanine residue was replaced by a valine, and in two, the trafficking defect was rescued by changing the valine to cysteine. One mutant protein (Q457R) did reach the plasma membrane, but it was unable to transport the sugar across the cell membrane. We conclude that mutations in the SGLT1 gene are the cause of glucose-galactose malabsorption, and sugar transport is impaired mainly because the mutant proteins are either truncated or are not targeted properly to the cell membrane.