{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:50:20Z","timestamp":1791978620246,"version":"4.4.0"},"reference-count":35,"publisher":"American Physiological Society","issue":"5","license":[{"start":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T00:00:00Z","timestamp":1629158400000},"content-version":"vor","delay-in-days":228,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DK19567"],"award-info":[{"award-number":["DK19567"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DK118640"],"award-info":[{"award-number":["DK118640"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009002","name":"Ministry of Education and Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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 V\u00e4sterbotten 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 \u03b1-methyl-D-glucopyranoside (\u03b1MDG). 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 V\u00e4sterbotten 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.<\/jats:p>","DOI":"10.1093\/function\/zqab040","type":"journal-article","created":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T09:11:59Z","timestamp":1629191519000},"source":"Crossref","is-referenced-by-count":7,"title":["The Molecular Basis of Glucose Galactose Malabsorption in a Large Swedish Pedigree"],"prefix":"10.1152","volume":"2","author":[{"given":"M Pilar","family":"Lostao","sequence":"first","affiliation":[{"name":"Departments of Physiology and Pediatrics, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1751, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald D","family":"Loo","sequence":"additional","affiliation":[{"name":"Department of Physiology, The Geffen School of Medicine, UCLA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olle","family":"Hernell","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Pediatrics, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1751, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Meeuwisse","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Pediatrics, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1751, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin G","family":"Martin","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Pediatrics, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1751, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernest M","family":"Wright","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Pediatrics, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1751, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","published-online":{"date-parts":[[2021,8,17]]},"reference":[{"issue":"5","key":"2021122118045352200_bib1","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat Genet"},{"issue":"8","key":"2021122118045352200_bib2","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1053\/j.gastro.2018.03.067","article-title":"Advances in evaluation of chronic diarrhea in infants","volume":"154","author":"Thiagarajah","year":"2018","journal-title":"Gastroenterology"},{"issue":"3","key":"2021122118045352200_bib3","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1056\/NEJMoa054288","article-title":"Mutant neurogenin-3 in congenital malabsorptive diarrhea","volume":"355","author":"Wang","year":"2006","journal-title":"N Engl J Med"},{"issue":"10","key":"2021122118045352200_bib4","first-page":"1163","article-title":"MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity","volume":"40","author":"Muller","year":"2008","journal-title":"NatGenet"},{"issue":"6","key":"2021122118045352200_bib5","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1111\/j.1651-2227.1962.tb06600.x","article-title":"Chronic diarrhoea caused by monosaccharide malabsorption","volume":"51","author":"Lindquist","year":"1962","journal-title":"Acta Paediatr"},{"key":"2021122118045352200_bib6","first-page":"895","article-title":"L'Intolerance aux sucres a transfert intestinal actif: ses rapports avec l'intol\u00e9rance au lactose et le syndrome coeliaque","volume-title":"Arch Fr Pediatr","author":"Laplane","year":"1962"},{"issue":"Suppl","key":"2021122118045352200_bib7","first-page":"181+","article-title":"Glucose-galactose malabsorption. 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