Submitted on June 1, 2006
Revised on July 19, 2006
Accepted on July 21, 2006
Conditional expression of human acid 
-glucosidase (GCase) in liver improves the visceral phenotype in a gaucher disease variant mouse model
Ying Sun, Brian Quinn, You-Hai Xu, Tatyana Leonova, David P. Witte, and Gregory A. Grabowski
Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
Corresponding Author: greg.grabowski{at}cchmc.org
The reversibility and regression of histological and biochemical findings in a mouse model of Gaucher disease (4L/PS-NA) was evaluated using a liver-enriched activator protein (LAP) promoter control of a tTA-responsive human acid 
-glucosidase (hGCase) transgenic system. 4L/PS-NA has the GCase V394L/V394L (4L) point mutation combined with hypomorphic (~6% wild type) expression of the mouse prosaposin transgene (PS-NA). The hGCase/4L/PS-NA had exclusive liver expression of hGCase controlled by doxycycline (DOX). In the absence of DOX, hGCase was secreted from liver at levels of ~120 
g /ml serum with only ~8% of full activity, following exposure to pH 7.4 in serum. The hGCase activity and protein were detected in cells of the liver (massive), lung and spleen, but not the brain. The visceral tissue storage cells and GC accumulation in hGCase/4L/PS-NA were decreased from that in 4L/PS-NA mice. Turning off hGCase expression with dietary DOX, led to re-accumulation of storage cells and of GC in liver, lung and spleen, and macrophage activation in those tissues. This study demonstrates that conditionally expressed hGCase supplemented the existing mutant mouse GCase to control visceral substrate accumulation in vivo.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
