A deletion in the Ctns gene causes renal tubular dysfunction and cystine accumulation in LEA/Tohm rats

Yukiko Shimizu, Rieko Yanobu-Takanashi, Kenta Nakano, Kenji Hamase, Toshiaki Shimizu, Tadashi Okamura

Research output: Contribution to journalArticle

Abstract

The Long-Evans Agouti (LEA/Tohm) rat has recently been established as a new rat model of type 2 diabetes. The onset of diabetes mellitus was observed only in male LEA/Tohm rats; however, urinary glucose appeared before the onset of diabetes. To clarify the genetic basis of urinary glucose, we performed genetic linkage analysis using (BN × LEA) F 2 intercross progeny. A recessively acting locus responsible for urinary glucose excretion (ugl) was mapped to a 7.9 Mb region of chromosome 10, which contains the cystinosin (Ctns) gene. The Ctns gene encodes the cystine transporter, which transports cystine out of the lysosome and is responsible for nephropathic cystinosis in humans. Sequence analysis identified a 13-bp deletion in the Ctns gene, leading to a truncated and loss-of-function protein, which cause cystine accumulation in various tissues. We also developed a novel congenic rat strain harboring the Ctns ugl mutation on the F344 genetic background. Phenotypic analysis of F344-Ctns ugl rats indicated that the incidence of urinary glucose was 100% in both males and females at around 40 weeks of age, and marked cystine accumulation was observed in the tissues, as well as remarkable renal lesions and cystine crystals in the lysosomes of the renal cortex. Furthermore, treatment with cysteamine depleted the cystine contents in F344-Ctns ugl rat embryonic fibroblasts. These results indicated that the F344-Ctns ugl rat provides a novel rat model of cystinosis, which allows not only a better understanding of the pathogenesis and pathophysiology of cystinosis but will also contribute to the development of new therapies.

Original languageEnglish
Pages (from-to)23-33
Number of pages11
JournalMammalian Genome
Volume30
Issue number1-2
DOIs
Publication statusPublished - Feb 13 2019

Fingerprint

Cystine
Kidney
Glucose
Cystinosis
Genes
Lysosomes
Cysteamine
Chromosomes, Human, Pair 10
Genetic Linkage
Type 2 Diabetes Mellitus
Sequence Analysis
Diabetes Mellitus
Fibroblasts
Mutation
Incidence

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

A deletion in the Ctns gene causes renal tubular dysfunction and cystine accumulation in LEA/Tohm rats. / Shimizu, Yukiko; Yanobu-Takanashi, Rieko; Nakano, Kenta; Hamase, Kenji; Shimizu, Toshiaki; Okamura, Tadashi.

In: Mammalian Genome, Vol. 30, No. 1-2, 13.02.2019, p. 23-33.

Research output: Contribution to journalArticle

Shimizu, Yukiko ; Yanobu-Takanashi, Rieko ; Nakano, Kenta ; Hamase, Kenji ; Shimizu, Toshiaki ; Okamura, Tadashi. / A deletion in the Ctns gene causes renal tubular dysfunction and cystine accumulation in LEA/Tohm rats. In: Mammalian Genome. 2019 ; Vol. 30, No. 1-2. pp. 23-33.
@article{6fb92b3680b644efa1b002e68274d346,
title = "A deletion in the Ctns gene causes renal tubular dysfunction and cystine accumulation in LEA/Tohm rats",
abstract = "The Long-Evans Agouti (LEA/Tohm) rat has recently been established as a new rat model of type 2 diabetes. The onset of diabetes mellitus was observed only in male LEA/Tohm rats; however, urinary glucose appeared before the onset of diabetes. To clarify the genetic basis of urinary glucose, we performed genetic linkage analysis using (BN × LEA) F 2 intercross progeny. A recessively acting locus responsible for urinary glucose excretion (ugl) was mapped to a 7.9 Mb region of chromosome 10, which contains the cystinosin (Ctns) gene. The Ctns gene encodes the cystine transporter, which transports cystine out of the lysosome and is responsible for nephropathic cystinosis in humans. Sequence analysis identified a 13-bp deletion in the Ctns gene, leading to a truncated and loss-of-function protein, which cause cystine accumulation in various tissues. We also developed a novel congenic rat strain harboring the Ctns ugl mutation on the F344 genetic background. Phenotypic analysis of F344-Ctns ugl rats indicated that the incidence of urinary glucose was 100{\%} in both males and females at around 40 weeks of age, and marked cystine accumulation was observed in the tissues, as well as remarkable renal lesions and cystine crystals in the lysosomes of the renal cortex. Furthermore, treatment with cysteamine depleted the cystine contents in F344-Ctns ugl rat embryonic fibroblasts. These results indicated that the F344-Ctns ugl rat provides a novel rat model of cystinosis, which allows not only a better understanding of the pathogenesis and pathophysiology of cystinosis but will also contribute to the development of new therapies.",
author = "Yukiko Shimizu and Rieko Yanobu-Takanashi and Kenta Nakano and Kenji Hamase and Toshiaki Shimizu and Tadashi Okamura",
year = "2019",
month = "2",
day = "13",
doi = "10.1007/s00335-018-9790-3",
language = "English",
volume = "30",
pages = "23--33",
journal = "Mammalian Genome",
issn = "0938-8990",
publisher = "Springer New York",
number = "1-2",

}

TY - JOUR

T1 - A deletion in the Ctns gene causes renal tubular dysfunction and cystine accumulation in LEA/Tohm rats

AU - Shimizu, Yukiko

AU - Yanobu-Takanashi, Rieko

AU - Nakano, Kenta

AU - Hamase, Kenji

AU - Shimizu, Toshiaki

AU - Okamura, Tadashi

PY - 2019/2/13

Y1 - 2019/2/13

N2 - The Long-Evans Agouti (LEA/Tohm) rat has recently been established as a new rat model of type 2 diabetes. The onset of diabetes mellitus was observed only in male LEA/Tohm rats; however, urinary glucose appeared before the onset of diabetes. To clarify the genetic basis of urinary glucose, we performed genetic linkage analysis using (BN × LEA) F 2 intercross progeny. A recessively acting locus responsible for urinary glucose excretion (ugl) was mapped to a 7.9 Mb region of chromosome 10, which contains the cystinosin (Ctns) gene. The Ctns gene encodes the cystine transporter, which transports cystine out of the lysosome and is responsible for nephropathic cystinosis in humans. Sequence analysis identified a 13-bp deletion in the Ctns gene, leading to a truncated and loss-of-function protein, which cause cystine accumulation in various tissues. We also developed a novel congenic rat strain harboring the Ctns ugl mutation on the F344 genetic background. Phenotypic analysis of F344-Ctns ugl rats indicated that the incidence of urinary glucose was 100% in both males and females at around 40 weeks of age, and marked cystine accumulation was observed in the tissues, as well as remarkable renal lesions and cystine crystals in the lysosomes of the renal cortex. Furthermore, treatment with cysteamine depleted the cystine contents in F344-Ctns ugl rat embryonic fibroblasts. These results indicated that the F344-Ctns ugl rat provides a novel rat model of cystinosis, which allows not only a better understanding of the pathogenesis and pathophysiology of cystinosis but will also contribute to the development of new therapies.

AB - The Long-Evans Agouti (LEA/Tohm) rat has recently been established as a new rat model of type 2 diabetes. The onset of diabetes mellitus was observed only in male LEA/Tohm rats; however, urinary glucose appeared before the onset of diabetes. To clarify the genetic basis of urinary glucose, we performed genetic linkage analysis using (BN × LEA) F 2 intercross progeny. A recessively acting locus responsible for urinary glucose excretion (ugl) was mapped to a 7.9 Mb region of chromosome 10, which contains the cystinosin (Ctns) gene. The Ctns gene encodes the cystine transporter, which transports cystine out of the lysosome and is responsible for nephropathic cystinosis in humans. Sequence analysis identified a 13-bp deletion in the Ctns gene, leading to a truncated and loss-of-function protein, which cause cystine accumulation in various tissues. We also developed a novel congenic rat strain harboring the Ctns ugl mutation on the F344 genetic background. Phenotypic analysis of F344-Ctns ugl rats indicated that the incidence of urinary glucose was 100% in both males and females at around 40 weeks of age, and marked cystine accumulation was observed in the tissues, as well as remarkable renal lesions and cystine crystals in the lysosomes of the renal cortex. Furthermore, treatment with cysteamine depleted the cystine contents in F344-Ctns ugl rat embryonic fibroblasts. These results indicated that the F344-Ctns ugl rat provides a novel rat model of cystinosis, which allows not only a better understanding of the pathogenesis and pathophysiology of cystinosis but will also contribute to the development of new therapies.

UR - http://www.scopus.com/inward/record.url?scp=85059161694&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059161694&partnerID=8YFLogxK

U2 - 10.1007/s00335-018-9790-3

DO - 10.1007/s00335-018-9790-3

M3 - Article

C2 - 30591971

AN - SCOPUS:85059161694

VL - 30

SP - 23

EP - 33

JO - Mammalian Genome

JF - Mammalian Genome

SN - 0938-8990

IS - 1-2

ER -