title: A missense mutation in the Na(+)/glucose cotransporter gene SGLT1 in a patient with congenital glucose-galactose malabsorption: normal trafficking but inactivation of the mutant protein.
abstract: The Na(+)/glucose cotransporter gene SGLT1 was analyzed in a Japanese patient with congenital glucose-galactose malabsorption. Genomic DNA was used as a template for amplification by the polymerase chain reaction of each of the 15 exons of SGLT1. The amplification products were cloned and sequenced. About half of the exon 5 clones of the patient contained a C-->T transition, resulting in an Arg(135)-->Trp mutation, whereas the remaining clones contained the normal exon 5 sequence. In addition, whereas some exon 12 clones exhibited the normal sequence, others showed a CAgtaggtatcatc-->CAgacc mutation at the splice donor site of intron 12 that may result either in the skipping of exon 12 or in read-through of intron 12. Neither the Arg(135)-->Trp mutant nor either of the possible intron 12 mutant proteins exhibited Na(+)-dependent glucose transport activity when expressed in Xenopus oocytes. Immunocytochemical analysis indicated, however, that the Arg(135)-->Trp mutant was localized to the oocyte plasma membrane. DNA sequence analysis revealed that the missense mutation in exon 5 and the splice site mutation in intron 12 were inherited from the proband's father and mother, respectively. These results indicate that the patient is a compound heterozygote for this disease, and that the Arg(135)-->Trp mutant of SGLT1 undergoes normal trafficking to the plasma membrane but is non-functional.
authors.affiliation: Laboratory of Biophysics, School of Medicine, Teikyo University, hachioji, Tokyo, Japan. kasahara@main.teikyo-u.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Kasahara
authors.forename: M
authors.initials: M
authors.lastname: Maeda
authors.forename: S
authors.initials: S
authors.lastname: Hayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Mori
authors.forename: T
authors.initials: T
authors.lastname: Abe
mesh_terms: D000818:Animals; D001483:Base Sequence; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D005690:Galactose / Q000172:deficiency / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D008286:Malabsorption Syndromes / Q000151:congenital* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D020125:Mutation, Missense; D009865:Oocytes / Q000378:metabolism; D010375:Pedigree; D051269:Sodium-Glucose Transporter 1; D014981:Xenopus
chemical_list: D008562:Membrane Glycoproteins; D009004:Monosaccharide Transport Proteins; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; D005947:Glucose; D005690:Galactose