Phenotypic analysis of seizure-prone mice lacking L-isoaspartate (D-aspartate) O-methyltransferase.

Abstract

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.

• Authors: E Kim, J D Lowenson, S Clarke, S G Young
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 274 Issue 29 Pg. 20671-8 (Jul 16 1999) ISSN: 0021-9258 [Print] United States
• PMID: 10400700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anticonvulsants
• Dipeptides
• isospaglumic acid
• Protein Methyltransferases
• Protein D-Aspartate-L-Isoaspartate Methyltransferase

Topics

• Animals
• Anticonvulsants (pharmacology, therapeutic use)
• Cell Division (genetics)
• Dipeptides (metabolism)
• Embryo, Mammalian (cytology)
• Female
• Male
• Mice
• Mice, Knockout
• Phenotype
• Protein D-Aspartate-L-Isoaspartate Methyltransferase
• Protein Methyltransferases (genetics, metabolism)
• Seizures (drug therapy, genetics, physiopathology)
• Sexual Behavior, Animal (drug effects)
• Substrate Specificity