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. 2018 Nov;41(6):1015-1025.
doi: 10.1007/s10545-018-0211-2. Epub 2018 Jul 2.

Development and characterization of an inducible mouse model for glycogen storage disease type Ib

Federica Raggi  1 , Anna Livia Pissavino  1 , Roberta Resaz  1 , Daniela Segalerba  1 , Andrea Puglisi  1 , Cristina Vanni  1 , Francesca Antonini  2 , Genny Del Zotto  2 , Alessandra Gamberucci  3 , Paola Marcolongo  3 , Maria Carla Bosco  1 , Federica Grillo  4   5 , Luca Mastracci  4   5 , Alessandra Eva  6
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Development and characterization of an inducible mouse model for glycogen storage disease type Ib

Federica Raggi et al. J Inherit Metab Dis. 2018 Nov.

Abstract

Background and aims: Glycogen storage disease type Ib (GSD1b) is a rare metabolic and immune disorder caused by a deficiency in the glucose-6-phosphate transporter (G6PT) and characterized by impaired glucose homeostasis, myeloid dysfunction, and long-term risk of hepatocellular adenomas. Despite maximal therapy, based on a strict diet and on granulocyte colony-stimulating factor treatment, long-term severe complications still develop. Understanding the pathophysiology of GSD1b is a prerequisite to develop new therapeutic strategies and depends on the availability of animal models. The G6PT-KO mouse mimics the human disease but is very fragile and rarely survives weaning. We generated a conditional G6PT-deficient mouse as an alternative model for studying the long-term pathophysiology of the disease. We utilized this conditional mouse to develop an inducible G6PT-KO model to allow temporally regulated G6PT deletion by the administration of tamoxifen (TM).

Methods: We generated a conditional G6PT-deficient mouse utilizing the CRElox strategy. Histology, histochemistry, and phenotype analyses were performed at different times after TM-induced G6PT inactivation. Neutrophils and monocytes were isolated and analyzed for functional activity with standard techniques.

Results: The G6PT-inducible KO mice display the expected disturbances of G6P metabolism and myeloid dysfunctions of the human disorder, even though with a milder intensity.

Conclusions: TM-induced inactivation of G6PT in these mice leads to a phenotype which mimics that of human GSD1b patients. The conditional mice we have generated represent an excellent tool to study the tissue-specific role of the G6PT gene and the mechanism of long-term complications in GSD1b.

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