title: Deficiency in protein L-isoaspartyl methyltransferase results in a fatal progressive epilepsy.
abstract: Protein L-isoaspartyl methyltransferase (PIMT) is suggested to play a role in the repair of aged protein spontaneously incorporated with isoaspartyl residues. We generated PIMT-deficient mice by targeted disruption of the PIMT gene to elucidate the biological role of the gene in vivo. PIMT-deficient mice died from progressive epileptic seizures with grand mal and myoclonus between 4 and 12 weeks of age. An anticonvulsive drug, dipropylacetic acid (DPA), improved their survival but failed to cure the fatal outcome. L-Isoaspartatate, the putative substrate for PIMT, was increased ninefold in the brains of PIMT-deficient mice. The brains of PIMT-deficient mice started to enlarge after 4 weeks of age when the apical dendrites of pyramidal neurons in cerebral cortices showed aberrant arborizations with disorganized microtubules. We conclude that methylation of modified proteins with isoaspartyl residues is essential for the maintenance of a mature CNS and that a deficiency in PIMT results in fatal progressive epilepsy in mice.
authors.affiliation: Department of Neurophysiology, Tokyo Metropolitan Institute of Gerontology, Tokyo-173, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Takagi
authors.forename: D
authors.initials: D
authors.lastname: Kitamura
authors.forename: H
authors.initials: H
authors.lastname: Tatsuoka
authors.forename: H
authors.initials: H
authors.lastname: Nakano
authors.forename: H
authors.initials: H
authors.lastname: Kawano
authors.forename: H
authors.initials: H
authors.lastname: Kuroyanagi
authors.forename: Y
authors.initials: Y
authors.lastname: Yahagi
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.forename: K
authors.initials: K
authors.lastname: Koizumi
authors.forename: T
authors.initials: T
authors.lastname: Sakai
authors.forename: K
authors.initials: K
authors.lastname: Saito
authors.forename: T
authors.initials: T
authors.lastname: Chiba
authors.forename: K
authors.initials: K
authors.lastname: Kawamura
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Mori
authors.forename: T
authors.initials: T
authors.lastname: Shirasawa
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004827:Epilepsy / Q000209:etiology* / Q000401:mortality / Q000503:physiopathology*; D004830:Epilepsy, Tonic-Clonic / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D010641:Phenotype; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase; D011496:Protein Methyltransferases / Q000172:deficiency* / Q000235:genetics; D013237:Stereoisomerism
chemical_list: D001224:Aspartic Acid; D011496:Protein Methyltransferases; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase