title: Global gene expression profile progression in Gaucher disease mouse models.
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.
authors.affiliation: The Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA. greg.grabowski@cchmc.org
authors.forename: You-Hai
authors.initials: YH
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Jia
authors.forename: Brian
authors.initials: B
authors.lastname: Quinn
authors.forename: Matthew
authors.initials: M
authors.lastname: Zamzow
authors.forename: Keith
authors.initials: K
authors.lastname: Stringer
authors.forename: Bruce
authors.initials: B
authors.lastname: Aronow
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Wujuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Kenneth D R
authors.initials: KD
authors.lastname: Setchell
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005776:Gaucher Disease / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D006028:Glycosphingolipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D006028:Glycosphingolipids