title: Novel frame-shift mutation in Slc5a2 encoding SGLT2 in a strain of senescence-accelerated mouse SAMP10.
abstract: The senescence-accelerated mouse prone10 (SAMP10) strain, a model of aging, exhibits cognitive impairments and cerebral atrophy. We noticed that SAMP10/TaSlc mice, a SAMP10 substrain, have developed persistent glucosuria over the past few years. In the present study, we characterized SAMP10/TaSlc mice and further identified a spontaneous mutation in the Slc5a2 gene encoding sodium-glucose co-transporter (SGLT) 2. The mean concentration of urine glucose was high in SAMP10/TaSlc mice and increased further with advancing age, whereas other strains of senescence-accelerated mice, including SAMP1/SkuSlc, SAMP6/TaSlc and SAMP8/TaSlc or normal aging control SAMR1/TaSlc mice, exhibited no detectable glucose in urine. SAMP10/TaSlc mice consumed increasing amounts of food and water compared to SAMR1/TaSlc mice, suggesting the compensation of polyuria and the loss of glucose. Oral glucose tolerance tests showed decreased glucose reabsorption in the kidney of SAMP10/TaSlc mice. In addition, blood glucose levels decreased in an age-dependent fashion. The kidney was innately larger than that of control mice with no histological alterations. We examined the expression levels of glucose transporters in the kidney. Among SGLT1, SGLT2, glucose transporter (GLUT) 1 and GLUT2, we found a significant decrease only in the level of SGLT2. DNA sequencing of SGLT2 in SAMP10/TaSlc mice revealed a single nucleotide deletion of guanine at 1236, which resulted in a frameshift mutation that produced a truncated protein. We designate this strain as SAMP10/TaSlc-Slc5a2(slc) (SAMP10-ΔSglt2). Recently, SGLT2 inhibitors have been demonstrated to be effective for the treatment of patients with type 2 diabetes (T2D). SAMP10-ΔSglt2 mice may serve as a unique preclinical model to study the link between aging-related neurodegenerative disorders and T2D.
authors.affiliation: Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. Electronic address: unno@u-shizuoka-ken.ac.jp.
authors.forename: Keiko
authors.initials: K
authors.lastname: Unno
authors.affiliation: Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
authors.forename: Masateru
authors.initials: M
authors.lastname: Toda
authors.affiliation: Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Hagiwara
authors.affiliation: Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Iguchi
authors.affiliation: Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Hoshino
authors.affiliation: School of Nursing, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Takabayashi
authors.affiliation: Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya, Kasugai, Aichi 480-0392, Japan.
authors.forename: Sanae
authors.initials: S
authors.lastname: Hasegawa-Ishii
authors.affiliation: Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya, Kasugai, Aichi 480-0392, Japan.
authors.forename: Atsuyoshi
authors.initials: A
authors.lastname: Shimada
authors.affiliation: Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya, Kasugai, Aichi 480-0392, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hosokawa
authors.affiliation: Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan; Department of Biological Sciences for Intractable Neurological Diseases, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Higuchi
authors.affiliation: Department of Advanced Medicine for Health Promotion, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mori
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D018388:Codon, Terminator / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D016368:Frameshift Mutation; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018388:Codon, Terminator; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D050505:Mutant Proteins; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; C495682:Slc2a2 protein, mouse; C495675:Slc5a1 protein, mouse; C490299:Slc5a2 protein, mouse; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2
keywords: Frame-shift mutation; Glucosuria; SAMP10; SGLT2; Senescence-accelerated mouse; Sodium-glucose co-transporter