Phenotypic analysis of seizure-prone mice lacking L-isoaspartate (D-aspartate) O-methyltransferase.
Within proteins and peptides, both L-asparaginyl and L-aspartyl residues spontaneously degrade, generating isomerized and racemized aspartyl residues. The enzyme protein L-isoaspartate (D-aspartate) O-methyltransferase (E.C. 2.1.1.77) initiates the conversion of L-isoaspartyl and D-aspartyl residues to normal L-aspartyl residues. This "repair" reaction helps to maintain proper protein conformation by preventing the accumulation of damaged proteins containing abnormal amino acid residues. Pcmt1-/- mice manifest two key phenotypes: a fatal seizure disorder and retarded growth. In this study, we characterized both phenotypes and demonstrated that they are linked. Continuous electroencephalogram monitoring of Pcmt1-/- mice revealed that abnormal cortical activity for approximately 50% of each 24-h period, even in mice that had no visible evidence of convulsions. The fatal seizure disorder in Pcmt1-/- mice can be mitigated but not eliminated by antiepileptic drugs. Interestingly, antiepileptic therapy normalized the growth of Pcmt1-/- mice, suggesting that the growth retardation is due to seizures rather than a global disturbance in growth at the cellular level. Consistent with this concept, the growth rate of Pcmt1-/- fibroblasts was indistinguishable from that of wild-type fibroblasts.
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94141-9100, USA. ekim@gladstone.ucsf.edu
E
E
Kim
J D
JD
Lowenson
S
S
Clarke
S G
SG
Young
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D002455:Cell Division / Q000235:genetics; D004151:Dipeptides / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase; D011496:Protein Methyltransferases / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D012726:Sexual Behavior, Animal / Q000187:drug effects; D013379:Substrate Specificity
D000927:Anticonvulsants; D004151:Dipeptides; C027172:isospaglumic acid; D011496:Protein Methyltransferases; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase