title: A missense mutation in kynurenine aminotransferase-1 in spontaneously hypertensive rats.
abstract: Spontaneously hypertensive rats (SHR) are the most extensively used animal model for genetic hypertension, increased stroke damage, and insulin resistance syndromes; however, the identification of target genes has proved difficult. SHR show elevated sympathetic nerve activity, and stimulation of the central blood pressure control centers with glutamate or nicotine results in exaggerated blood pressure responses, effects that appear to be genetically determined. Kynurenic acid, a competitive glutamate antagonist and a non-competitive nicotinic antagonist, can be synthesized in the brain by the enzyme kynurenine aminotransferase-1 (KAT-1). We have previously shown that KAT-1 activity is significantly reduced in SHR compared with normotensive Wistar Kyoto rats (WKY). Here we show that KAT-1 contains a missense mutation, E61G, in all the strains of SHR examined but not in any of the WKY or outbred strains. Previous studies on F2 rats from a cross of stroke-prone SHR and WKY have shown a suggestive level of linkage between elevated blood pressure and the KAT-1 locus on chromosome 3. In addition, the mutant enzyme expressed in Escherichia coli displays altered kinetics. This mutation may explain the enhanced sensitivity to glutamate and nicotine seen in SHR that may be related to an underlying mechanism of hypertension and increased sensitivity to stroke.
authors.affiliation: Garvan Institute of Medical Research, Sydney, 2010 Australia.
authors.forename: John B J
authors.initials: JB
authors.lastname: Kwok
authors.forename: Ranjna
authors.initials: R
authors.lastname: Kapoor
authors.forename: Takanari
authors.initials: T
authors.lastname: Gotoda
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Yoko
authors.initials: Y
authors.lastname: Iizuka
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.forename: Kim E
authors.initials: KE
authors.lastname: Isaacs
authors.forename: Virag V
authors.initials: VV
authors.lastname: Kushwaha
authors.forename: W Bret
authors.initials: WB
authors.lastname: Church
authors.forename: Peter R
authors.initials: PR
authors.lastname: Schofield
authors.forename: Vimal
authors.initials: V
authors.lastname: Kapoor
mesh_terms: D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000378:metabolism; D007700:Kinetics; D007736:Kynurenic Acid / Q000378:metabolism; D009154:Mutation; D020125:Mutation, Missense; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D000637:Transaminases / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase; D007736:Kynurenic Acid