Abstract
Glucose-galactose malabsorption (GGM) is due to mutations in the gene coding for the intestinal sodium glucose cotransporter SGLT1 (SLC5A1). Here we identify the rare variant Gln457Arg (Q457R) in a large pedigree of patients in the Västerbotten County in Northern Sweden with the clinical phenotype of GGM. The functional effect of the Q457R mutation was determined in protein expressed in Xenopus laevis oocytes using biophysical and biochemical methods. The mutant failed to transport the specific SGLT1 sugar analog α-methyl-D-glucopyranoside (αMDG). Q457R SGLT1 was synthesized in amounts comparable to the wild-type (WT) transporter. SGLT1 charge measurements and freeze-fracture electron microscopy demonstrated that the mutant protein was inserted into the plasma membrane. Electrophysiological experiments, both steady-state and presteady-state, demonstrated that the mutant bound sugar with an affinity lower than the WT transporter. Together with our previous studies on Q457C and Q457E mutants, we established that the positive charge on Q457R prevented the translocation of sugar from the outward-facing to inward-facing conformation. This is contrary to other GGM cases where missense mutations caused defects in trafficking SGLT1 to the plasma membrane. Thirteen GGM patients are now added to the pedigree traced back to the late 17th century. The frequency of the Q457R variant in Västerbotten County genomes, 0.0067, is higher than in the general Swedish population, 0.0015, and higher than the general European population, 0.000067. This explains the high number of GGM cases in this region of Sweden.
Highlights
Next-generation sequencing has rapidly improved the ability to identify novel monogenic disorders, including congenital diarrheas and enteropathies (CODE) in young infants.[1,2] Chronic CODE disorders are generally classified as either secretory diarrheas resulting from abnormal electrolyte transport or malabsorptive diarrheas caused by failure to absorb nutrients
We established that Glucose-galactose malabsorption (GGM) is due to mutations in the gene coding for the intestinal brush border sodium glucose cotransporter SGLT1 (SLC5A1).[9,10,11,12,13]
Molecular analysis of the SGLT1 (SLC5A1) gene in 9 GGM patients (1, 9, 10, 11, 12, 15, 16, and 17) revealed a variant exon 12 by single-stranded conformational polymorphism (SSCP), and sequencing of the exon in both alleles showed a CAG to CGG mutation at nucleotide 1380 resulting in a Q457R mutation (Figure 2)
Summary
Next-generation sequencing has rapidly improved the ability to identify novel monogenic disorders, including congenital diarrheas and enteropathies (CODE) in young infants.[1,2] Chronic CODE disorders are generally classified as either secretory diarrheas resulting from abnormal electrolyte transport or malabsorptive diarrheas caused by failure to absorb nutrients. The first CODE disorder described at both a clinical and molecular level was glucose-galactose malabsorption (GGM), a potentially lethal defect in intestinal sugar absorption, was independently reported in 1962.5,6 Subsequently, this clinical phenotype was identified in 6 cases within a pedigree located in Northern Sweden.[7,8] A simple therapy, removing glucose, galactose, and lactose (and starch from older infants) from the diet, effectively treated these patients. The most common defect of Na+/glucose cotransport amongst the missense mutations is a failure to insert the transporter into the plasma membrane.[14] We were intrigued about the cause of GGM in the Vasterbotten pedigree traced back to the end of the 17th century (Figure 1).[7,8] We were fortunate to obtain a blood sample from the first case identified on the pedigree, 8 others diagnosed with the disorder and a few first-degree relatives. Examining whole-genome sequences of a control Vasterbotten population revealed a higher frequency of the Q457C variant than in the general Swedish and European populations
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