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dc.creatorLostao, M.P. (María Pilar)-
dc.creatorLoo, D.D. (Donald D.)-
dc.creatorHernell, O. (Olle)-
dc.creatorMeeuwisse, G. (Gunnar)-
dc.creatorMartin, M.G. (Martin G.)-
dc.creatorWright, E.M. (Ernest M.)-
dc.date.accessioned2021-09-30T06:37:14Z-
dc.date.available2021-09-30T06:37:14Z-
dc.date.issued2021-
dc.identifier.citationLostao-Crespo, M. (María del Pilar); Loo, D. D.; Hernell, O.; et al. "The molecular basis of glucose galactose malabsorption in a large Swedish pedigree". Function. 2 (5), 2021, zqab040es
dc.identifier.issn2633-8823-
dc.identifier.urihttps://hdl.handle.net/10171/62116-
dc.description.abstractGlucose-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 Vasterbotten 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 alpha-methyl-D-glucopyranoside (alphaMDG). 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 Vasterbotten County genomes, 0.0067, is higher than in the general Swedish population, 0.0015...-
dc.description.sponsorshipThis study was supported by grants from the NIH (EMW, DK19567 and MGM, DK118640) and funds from the Mellinkoff Endow- ment. MPL was supported by a Fellowship from the Ministry of Education and Science, Spain.-
dc.language.isoen-
dc.rightsinfo:eu-repo/semantics/openAccess-
dc.subjectSodium glucose cotransporter-
dc.subjectSGLT1-
dc.subjectGlucose-galactose malabsorption Swedish GGM pedigree-
dc.subjectGGM mutation SGLT1 structure-
dc.titleThe molecular basis of glucose galactose malabsorption in a large Swedish pedigree-
dc.typeinfo:eu-repo/semantics/article-
dc.description.noteThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/)-
dc.identifier.doi10.1093/function/zqab040-
dadun.citation.number5-
dadun.citation.publicationNameFunction-
dadun.citation.startingPagezqab040-
dadun.citation.volume2-

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