title: Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice.
abstract: Thymidine phosphorylase (TP) regulates intracellular and plasma thymidine levels. TP deficiency is hypothesized to (i) increase levels of thymidine in plasma, (ii) lead to mitochondrial DNA alterations, and (iii) cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In order to elucidate the physiological roles of TP, we generated mice deficient in the TP gene. Although TP activity in the liver was inhibited in these mice, it was fully maintained in the small intestine. Murine uridine phosphorylase (UP), unlike human UP, cleaves thymidine, as well as uridine. We therefore generated TP-UP double-knockout (TP(-/-) UP(-/-)) mice. TP activities were inhibited in TP(-/-) UP(-/-) mice, and the level of thymidine in the plasma of TP(-/-) UP(-/-) mice was higher than for TP(-/-) mice. Unexpectedly, we could not observe alterations of mitochondrial DNA or pathological changes in the muscles of the TP(-/-) UP(-/-) mice, even when these mice were fed thymidine for 7 months. However, we did find hyperintense lesions on magnetic resonance T(2) maps in the brain and axonal edema by electron microscopic study of the brain in TP(-/-) UP(-/-) mice. These findings suggested that the inhibition of TP activity caused the elevation of pyrimidine levels in plasma and consequent axonal swelling in the brains of mice. Since lesions in the brain do not appear to be due to mitochondrial alterations and pathological changes in the muscle were not found, this model will provide further insights into the causes of MNGIE.
authors.affiliation: Department of Cancer Chemotherapy, Institute for Cancer Research, Third Department of Internal Medicin, Kagoshima University, 8-35-1 Sakura-gaoka, Kagoshima 890-8520, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Haraguchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tsujimoto
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fukushima
authors.forename: Itsuro
authors.initials: I
authors.lastname: Higuchi
authors.forename: Hideto
authors.initials: H
authors.lastname: Kuribayashi
authors.forename: Hideo
authors.initials: H
authors.lastname: Utsumi
authors.forename: Atsuo
authors.initials: A
authors.lastname: Nakayama
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hashizume
authors.forename: Junko
authors.initials: J
authors.lastname: Hirato
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Hamano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Ishikawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Toyoshima
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kaname
authors.forename: Masaharu
authors.initials: M
authors.lastname: Komatsu
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
authors.forename: Takenari
authors.initials: T
authors.lastname: Gotanda
authors.forename: Tokushi
authors.initials: T
authors.lastname: Tachiwada
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Sumizawa
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Miyadera
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Osame
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamada
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Akiyama
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D018390:Gene Targeting; D006801:Humans; D007421:Intestine, Small / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D013939:Thymidine Phosphorylase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014543:Uridine Phosphorylase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D014543:Uridine Phosphorylase; D013939:Thymidine Phosphorylase