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Open Access Research article

Global gene expression profile progression in Gaucher disease mouse models

You-Hai Xu1, Li Jia1, Brian Quinn1, Matthew Zamzow1, Keith Stringer2, Bruce Aronow3, Ying Sun1, Wujuan Zhang2, Kenneth DR Setchell2 and Gregory A Grabowski1*

Author Affiliations

1 The Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA

2 The Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA

3 The Division of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA

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BMC Genomics 2011, 12:20  doi:10.1186/1471-2164-12-20

Published: 11 January 2011

Abstract

Background

Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure.

Results

To elucidate this pathogenic pathway, developmental global gene expression analyses were conducted in distinct Gba1 point-mutated mice (V394L/V394L and D409 V/null). About 0.9 to 3% of genes had altered expression patterns (≥ ± 1.8 fold change), representing several categories, but particularly macrophage activation and immune response genes. Time course analyses (12 to 28 wk) of INFγ-regulated pro-inflammatory (13) and IL-4-regulated anti-inflammatory (11) cytokine/mediator networks showed tissue differential profiles in the lung and liver of the Gba1 mutant mice, implying that the lipid-storage macrophages were not functionally inert. The time course alterations of the INFγ and IL-4 pathways were similar, but varied in degree in these tissues and with the Gba1 mutation.

Conclusions

Biochemical and pathological analyses demonstrated direct relationships between the degree of tissue glucosylceramides and the gene expression profile alterations. These analyses implicate IFNγ-regulated pro-inflammatory and IL-4-regulated anti-inflammatory networks in differential disease progression with implications for understanding the Gaucher disease course and pathophysiology.