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.