Lessons from new mouse models of glycogen storage disease type 1a in relation to the time course and organ specificity of the disease
Résumé
Patients with glycogen storage diseases type 1 (GSD1) suffer from life-threatening
hypoglycaemia, when left untreated. Despite an intensive dietary treatment, patients develop
severe complications, such as liver tumors and renal failure, with aging. Until now, the animal
models available for studying the GSD1 did not survive after weaning. To gain further
insights into the molecular mechanisms of the disease and to evaluate potential treatment
strategies, we have recently developed novel mouse models in which the catalytic subunit of
glucose-6 phosphatase (G6pc) is deleted in each glucose-producing organ specifically. For
that, B6.G6pcex3lox/ex3lox mice were crossed with transgenic mice expressing a recombinase
under the control of the serum albumin, the kidney androgen protein or the villin promoter, in
order to obtain liver, kidney or intestine G6pc-/- mice, respectively.
As opposed to total G6pc knockout mice, tissue-specific G6pc deficiency allows mice
to maintain their blood glucose by inducing glucose production in the other gluconeogenic
organs. Even though it is considered that glucose is produced mainly by the liver, liver G6pc-/-
mice are perfectly viable and exhibit the same hepatic pathological features as GSD1 patients,
including the late development of hepatocellular adenomas and carcinomas. Interestingly,
renal G6pc-/- mice developed renal symptoms similar to the early human GSD1 nephropathy.
This includes glycogen overload that leads to nephromegaly and morphological and
functional alterations in the kidneys. Thus, our data suggest that renal G6Pase deficiency per
se is sufficient to induce the renal pathology of GSD1.
Therefore, these new mouse models should allow us to improve the strategies of
treatment on both nutritional and pharmacological points of view.
Domaines
Neurosciences [q-bio.NC]
Origine : Fichiers produits par l'(les) auteur(s)
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