Novel frame-shift mutation in Slc5a2 encoding SGLT2 in a strain of senescence-accelerated mouse SAMP10

Keiko Unno, Hiroyuki Yamamoto, Masateru Toda, Shiori Hagiwara, Kazuaki Iguchi, Minoru Hoshino, Fumiyo Takabayashi, Sanae Ishii, Atsuyoshi Shimada, Masanori Hosokawa, Keiichi Higuchi, Masayuki Mori

Research output: Contribution to journalArticle

4 Citations (Scopus)

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-Slc5a2slc (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.

Original languageEnglish (US)
Pages (from-to)89-94
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume454
Issue number1
DOIs
StatePublished - Nov 7 2014

Fingerprint

Frameshift Mutation
Glucose
Facilitative Glucose Transport Proteins
Aging of materials
Medical problems
Symporters
Gene encoding
Guanine
Blood Glucose
Nucleotides
Sodium
Water
DNA
Kidney
Type 2 Diabetes Mellitus
Sodium-Glucose Transporter 2
Proteins
Urine

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Unno, Keiko ; Yamamoto, Hiroyuki ; Toda, Masateru ; Hagiwara, Shiori ; Iguchi, Kazuaki ; Hoshino, Minoru ; Takabayashi, Fumiyo ; Ishii, Sanae ; Shimada, Atsuyoshi ; Hosokawa, Masanori ; Higuchi, Keiichi ; Mori, Masayuki. / Novel frame-shift mutation in Slc5a2 encoding SGLT2 in a strain of senescence-accelerated mouse SAMP10. In: Biochemical and Biophysical Research Communications. 2014 ; Vol. 454, No. 1. pp. 89-94.
@article{feb5f922a89b42b197a3cca435d0ccc3,
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-Slc5a2slc (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.",
author = "Keiko Unno and Hiroyuki Yamamoto and Masateru Toda and Shiori Hagiwara and Kazuaki Iguchi and Minoru Hoshino and Fumiyo Takabayashi and Sanae Ishii and Atsuyoshi Shimada and Masanori Hosokawa and Keiichi Higuchi and Masayuki Mori",
year = "2014",
month = "11",
day = "7",
doi = "10.1016/j.bbrc.2014.10.039",
language = "English (US)",
volume = "454",
pages = "89--94",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "1",

}

Unno, K, Yamamoto, H, Toda, M, Hagiwara, S, Iguchi, K, Hoshino, M, Takabayashi, F, Ishii, S, Shimada, A, Hosokawa, M, Higuchi, K & Mori, M 2014, 'Novel frame-shift mutation in Slc5a2 encoding SGLT2 in a strain of senescence-accelerated mouse SAMP10', Biochemical and Biophysical Research Communications, vol. 454, no. 1, pp. 89-94. https://doi.org/10.1016/j.bbrc.2014.10.039

Novel frame-shift mutation in Slc5a2 encoding SGLT2 in a strain of senescence-accelerated mouse SAMP10. / Unno, Keiko; Yamamoto, Hiroyuki; Toda, Masateru; Hagiwara, Shiori; Iguchi, Kazuaki; Hoshino, Minoru; Takabayashi, Fumiyo; Ishii, Sanae; Shimada, Atsuyoshi; Hosokawa, Masanori; Higuchi, Keiichi; Mori, Masayuki.

In: Biochemical and Biophysical Research Communications, Vol. 454, No. 1, 07.11.2014, p. 89-94.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel frame-shift mutation in Slc5a2 encoding SGLT2 in a strain of senescence-accelerated mouse SAMP10

AU - Unno, Keiko

AU - Yamamoto, Hiroyuki

AU - Toda, Masateru

AU - Hagiwara, Shiori

AU - Iguchi, Kazuaki

AU - Hoshino, Minoru

AU - Takabayashi, Fumiyo

AU - Ishii, Sanae

AU - Shimada, Atsuyoshi

AU - Hosokawa, Masanori

AU - Higuchi, Keiichi

AU - Mori, Masayuki

PY - 2014/11/7

Y1 - 2014/11/7

N2 - 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-Slc5a2slc (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.

AB - 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-Slc5a2slc (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.

UR - http://www.scopus.com/inward/record.url?scp=84910114493&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84910114493&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2014.10.039

DO - 10.1016/j.bbrc.2014.10.039

M3 - Article

C2 - 25450362

AN - SCOPUS:84910114493

VL - 454

SP - 89

EP - 94

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 1

ER -