The molecular basis of glucose galactose malabsorption in a large Swedish pedigree

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 Vasterbotten County in Northern Sweden with the clinical phenotype o...

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Autores: Lostao-Crespo, M.P. (María Pilar)|||/items/0c37f16e-d88c-407f-8cf7-18042cd3cfa9, Loo, D.D. (Donald D.)|||/items/057934f5-3c54-48d0-9ade-1babc698479a, Hernell, O. (Olle)|||/items/f0789266-e01f-4630-835d-ca04592397e8, Meeuwisse, G. (Gunnar)|||/items/f41b4203-92d1-4f01-abfe-0ce778bcfc14, Martin, M.G. (Martin G.)|||/items/784250c2-1c05-43bc-b19d-22154dd9ce8f, Wright, E.M. (Ernest M.)|||/items/abe8fe3f-2d6f-414c-9660-fab3a4be05f5
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/62116
Acceso en línea:https://hdl.handle.net/10171/62116
Access Level:acceso abierto
Palabra clave:Sodium glucose cotransporter
SGLT1
Glucose-galactose malabsorption Swedish GGM pedigree
GGM mutation SGLT1 structure
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spelling The molecular basis of glucose galactose malabsorption in a large Swedish pedigreeLostao-Crespo, M.P. (María Pilar)|||/items/0c37f16e-d88c-407f-8cf7-18042cd3cfa9Loo, D.D. (Donald D.)|||/items/057934f5-3c54-48d0-9ade-1babc698479aHernell, O. (Olle)|||/items/f0789266-e01f-4630-835d-ca04592397e8Meeuwisse, G. (Gunnar)|||/items/f41b4203-92d1-4f01-abfe-0ce778bcfc14Martin, M.G. (Martin G.)|||/items/784250c2-1c05-43bc-b19d-22154dd9ce8fWright, E.M. (Ernest M.)|||/items/abe8fe3f-2d6f-414c-9660-fab3a4be05f5Sodium glucose cotransporterSGLT1Glucose-galactose malabsorption Swedish GGM pedigreeGGM mutation SGLT1 structureGlucose-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...Dadun. Depósito Académico Digital Universidad de Navarra20212021-09-3020212021-01-0120212021-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/62116reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/621162026-06-21T12:47:57Z
dc.title.none.fl_str_mv The molecular basis of glucose galactose malabsorption in a large Swedish pedigree
title The molecular basis of glucose galactose malabsorption in a large Swedish pedigree
spellingShingle The molecular basis of glucose galactose malabsorption in a large Swedish pedigree
Lostao-Crespo, M.P. (María Pilar)|||/items/0c37f16e-d88c-407f-8cf7-18042cd3cfa9
Sodium glucose cotransporter
SGLT1
Glucose-galactose malabsorption Swedish GGM pedigree
GGM mutation SGLT1 structure
title_short The molecular basis of glucose galactose malabsorption in a large Swedish pedigree
title_full The molecular basis of glucose galactose malabsorption in a large Swedish pedigree
title_fullStr The molecular basis of glucose galactose malabsorption in a large Swedish pedigree
title_full_unstemmed The molecular basis of glucose galactose malabsorption in a large Swedish pedigree
title_sort The molecular basis of glucose galactose malabsorption in a large Swedish pedigree
dc.creator.none.fl_str_mv Lostao-Crespo, M.P. (María Pilar)|||/items/0c37f16e-d88c-407f-8cf7-18042cd3cfa9
Loo, D.D. (Donald D.)|||/items/057934f5-3c54-48d0-9ade-1babc698479a
Hernell, O. (Olle)|||/items/f0789266-e01f-4630-835d-ca04592397e8
Meeuwisse, G. (Gunnar)|||/items/f41b4203-92d1-4f01-abfe-0ce778bcfc14
Martin, M.G. (Martin G.)|||/items/784250c2-1c05-43bc-b19d-22154dd9ce8f
Wright, E.M. (Ernest M.)|||/items/abe8fe3f-2d6f-414c-9660-fab3a4be05f5
author Lostao-Crespo, M.P. (María Pilar)|||/items/0c37f16e-d88c-407f-8cf7-18042cd3cfa9
author_facet Lostao-Crespo, M.P. (María Pilar)|||/items/0c37f16e-d88c-407f-8cf7-18042cd3cfa9
Loo, D.D. (Donald D.)|||/items/057934f5-3c54-48d0-9ade-1babc698479a
Hernell, O. (Olle)|||/items/f0789266-e01f-4630-835d-ca04592397e8
Meeuwisse, G. (Gunnar)|||/items/f41b4203-92d1-4f01-abfe-0ce778bcfc14
Martin, M.G. (Martin G.)|||/items/784250c2-1c05-43bc-b19d-22154dd9ce8f
Wright, E.M. (Ernest M.)|||/items/abe8fe3f-2d6f-414c-9660-fab3a4be05f5
author_role author
author2 Loo, D.D. (Donald D.)|||/items/057934f5-3c54-48d0-9ade-1babc698479a
Hernell, O. (Olle)|||/items/f0789266-e01f-4630-835d-ca04592397e8
Meeuwisse, G. (Gunnar)|||/items/f41b4203-92d1-4f01-abfe-0ce778bcfc14
Martin, M.G. (Martin G.)|||/items/784250c2-1c05-43bc-b19d-22154dd9ce8f
Wright, E.M. (Ernest M.)|||/items/abe8fe3f-2d6f-414c-9660-fab3a4be05f5
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Dadun. Depósito Académico Digital Universidad de Navarra
dc.subject.none.fl_str_mv Sodium glucose cotransporter
SGLT1
Glucose-galactose malabsorption Swedish GGM pedigree
GGM mutation SGLT1 structure
topic Sodium glucose cotransporter
SGLT1
Glucose-galactose malabsorption Swedish GGM pedigree
GGM mutation SGLT1 structure
description 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 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...
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-09-30
2021
2021-01-01
2021
2021-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10171/62116
url https://hdl.handle.net/10171/62116
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra
instname:Universidad de Navarra
instname_str Universidad de Navarra
reponame_str Dadun. Depósito Académico Digital de la Universidad de Navarra
collection Dadun. Depósito Académico Digital de la Universidad de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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