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Function (Oxf) 2021 Jan 01;25:zqab040. doi: 10.1093/function/zqab040.
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The Molecular Basis of Glucose Galactose Malabsorption in a Large Swedish Pedigree.

Lostao MP , Loo DD , Hernell O , Meeuwisse G , Martin MG , Wright EM .

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.

PubMed ID: 34485913
Article link: Function (Oxf)
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: ran slc5a1.2
GO keywords: glucose transmembrane transporter activity

Disease Ontology terms: glucose metabolism disease [+]

Article Images: [+] show captions
References [+] :
Ameur, SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population. 2017, Pubmed