RGD Reference Report - A mouse model of L-2-hydroxyglutaric aciduria, a disorder of metabolite repair. - Rat Genome Database

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A mouse model of L-2-hydroxyglutaric aciduria, a disorder of metabolite repair.

Authors: Rzem, Rim  Achouri, Younes  Marbaix, Etienne  Schakman, Olivier  Wiame, Elsa  Marie, Sandrine  Gailly, Philippe  Vincent, Marie-Françoise  Veiga-da-Cunha, Maria  Van Schaftingen, Emile 
Citation: Rzem R, etal., PLoS One. 2015 Mar 12;10(3):e0119540. doi: 10.1371/journal.pone.0119540. eCollection 2015.
RGD ID: 13506815
Pubmed: PMID:25763823   (View Abstract at PubMed)
PMCID: PMC4357467   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0119540   (Journal Full-text)

The purpose of the present work was to progress in our understanding of the pathophysiology of L-2-hydroxyglutaric aciduria, due to a defect in L-2-hydroxyglutarate dehydrogenase, by creating and studying a mouse model of this disease. L-2-hydroxyglutarate dehydrogenase-deficient mice (l2hgdh-/-) accumulated L-2-hydroxyglutarate in tissues, most particularly in brain and testis, where the concentration reached ˜ 3.5 µmol/g. Male mice showed a 30% higher excretion of L-2-hydroxyglutarate compared to female mice, supporting that this dicarboxylic acid is partially made in males by lactate dehydrogenase C, a poorly specific form of this enzyme exclusively expressed in testes. Involvement of mitochondrial malate dehydrogenase in the formation of L-2-hydroxyglutarate was supported by the commensurate decrease in the formation of this dicarboxylic acid when down-regulating this enzyme in mouse l2hgdh-/- embryonic fibroblasts. The concentration of lysine and arginine was markedly increased in the brain of l2hgdh-/- adult mice. Saccharopine was depleted and glutamine was decreased by ˜ 40%. Lysine-α-ketoglutarate reductase, which converts lysine to saccharopine, was inhibited by L-2-hydroxyglutarate with a Ki of ˜ 0.8 mM. As low but significant activities of the bifunctional enzyme lysine-α-ketoglutarate reductase/saccharopine dehydrogenase were found in brain, these findings suggest that the classical lysine degradation pathway also operates in brain and is inhibited by the high concentrations of L-2-hydroxyglutarate found in l2hgdh-/- mice. Pathological analysis of the brain showed significant spongiosis. The vacuolar lesions mostly affected oligodendrocytes and myelin sheats, as in other dicarboxylic acidurias, suggesting that the pathophysiology of this model of leukodystrophy may involve irreversible pumping of a dicarboxylate in oligodendrocytes. Neurobehavioral testing indicated that the mice mostly suffered from a deficit in learning capacity. In conclusion, the findings support the concept that L-2-hydroxyglutaric aciduria is a disorder of metabolite repair. The accumulation of L-2-hydroxyglutarate exerts toxic effects through various means including enzyme inhibition and glial cell swelling.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
2-hydroxyglutaric aciduria  ISOL2hgdh (Mus musculus)13506815; 13506815 RGD 
2-hydroxyglutaric aciduria  IMP 13506815 RGD 

Objects Annotated

Genes (Rattus norvegicus)
L2hgdh  (L-2-hydroxyglutarate dehydrogenase)

Genes (Mus musculus)
L2hgdh  (L-2-hydroxyglutarate dehydrogenase)

Genes (Homo sapiens)
L2HGDH  (L-2-hydroxyglutarate dehydrogenase)


Additional Information