Generation and characterization of murine (Mus musculus L.1758 ) L-arginine:glycine amidinotransferase and guanidinoacetate N-methyl transferase knockout models to study human creatine deficiency syndromes

Abstract

GAMT-/- and AGAT-/- deficient mice have been demonstrated to be valuable models for better understanding the pathophysiology underlying human creatine deficiency syndromes, as both recapitulated the human disorders at the biochemical and physiological levels; however, severe impairment of neurological functions such as seizures or dyskinetic movements were not observed. In addition, by comparing the phenotypes and treatment responses to Cr supplementation the models provided an excellent possibility to explore as yet unrecognized functions of Cr, which would be impossible to realize in humans patients because Cr would be easily obtained from the food during adulthood or from maternofetal transport during embryonic development. Although the phenotypes suggested a role for Cr during development, fertility, nutrition, skeletal and cardiac muscle metabolism and performance as well as somatic body growth, the specific mechanistic reasons are yet to be elucidated. By comparing the three human diseases, in particular by looking at GAMT differential symptomatology and treatment responses to lowering of GAA, we have learned that accumulation of reactive guanidino compounds clearly mediates a subset of the symptoms in GAMT deficiency such as therapy-refractory epileptic seizures and extrapyramidal movement disorder, and that AGAT upregulation underlies such pathognomonic feature. Finally, strong evidence indicated that Cr/PCr play important roles in brain function, muscle metabolism, spermatogenesis and proper development of the offspring, as the phenotypes could be rescued by Cr in mice and humans. The fact that some of the complications could not be completely ameliorated unless Cr supplementation started early enough, as it was the case with brain dysfunction in humans and somatic body growth in mice, suggested that Cr is important for the early establishment and proper prenatal/postnatal development of those organs responsible for brain function and somatic growth.