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Magnetic resonance imaging reveals specific anatomical changes in the brain of Agat- and Gamt-mice attributed to creatine depletion and guanidinoacetate alteration.
Sinha, Ankit; Ahmed, Sohail; George, Chris; Tsagaris, Melina; Naufer, Amriya; von Both, Ingo; Tkachyova, Ilona; van Eede, Matthijs; Henkelman, Mark; Schulze, Andreas.
Afiliação
  • Sinha A; Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Ahmed S; Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
  • George C; Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Tsagaris M; Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Naufer A; Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
  • von Both I; Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Tkachyova I; Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
  • van Eede M; Mouse Imaging Centre, Toronto Center of Phenogenomics, Toronto, Ontario, Canada.
  • Henkelman M; Mouse Imaging Centre, Toronto Center of Phenogenomics, Toronto, Ontario, Canada.
  • Schulze A; Neurosciences and Mental Health Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
J Inherit Metab Dis ; 43(4): 827-842, 2020 07.
Article em En | MEDLINE | ID: mdl-31951021
ABSTRACT
Arginineglycine amidinotransferase- and guanidinoacetate methyltransferase deficiency are severe neurodevelopmental disorders. It is not known whether mouse models of disease express a neuroanatomical phenotype. High-resolution magnetic resonance imaging (MRI) with advanced image analysis was performed in perfused, fixed mouse brains encapsulated with the skull from male, 10-12 week old Agat -exc and B6J.Cg-Gamt tm1Isb mice (n = 48; n = 8 per genotype, strain). T2-weighted MRI scans were nonlinearly aligned to a 3D atlas of the mouse brain with 62 structures identified. Local differences in brain shape related to genotype were assessed by analysis of deformation fields. Creatine (Cr) and guanidinoacetate (GAA) were measured with high-performance liquid chromatography (HPLC) in brain homogenates (n = 24; n = 4 per genotype, strain) after whole-body perfusion. Cr was decreased in the brain of Agat- and Gamt mutant mice. GAA was decreased in Agat-/- and increased in Gamt-/- . Body weight and brain volume were lower in Agat-/- than in Gamt-/- . The analysis of entire brain structures revealed corpus callosum, internal capsule, fimbria and hypothalamus being different between the genotypes in both strains. Eighteen and fourteen significant peaks (local areas of difference in relative size) were found in Agat- and Gamt mutants, respectively. Comparing Agat-/- with Gamt-/- , we found changes in three brain regions, lateral septum, amygdala, and medulla. Intra-strain differences in four brain structures can be associated with Cr deficiency, while the inter-strain differences in three brain structures of the mutant mice may relate to GAA. Correlating these neuroanatomical findings with gene expression data implies the role of Cr metabolism in the developing brain and the importance of early intervention in patients with Cr deficiency syndromes.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Encéfalo / Metilases de Modificação do DNA / Creatina / Proteínas Supressoras de Tumor / Enzimas Reparadoras do DNA / Guanidinoacetato N-Metiltransferase / Glicina Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Encéfalo / Metilases de Modificação do DNA / Creatina / Proteínas Supressoras de Tumor / Enzimas Reparadoras do DNA / Guanidinoacetato N-Metiltransferase / Glicina Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article