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Blood Cells Mol Dis. 2011 Jan 15;46(1):4-10. doi: 10.1016/j.bcmd.2010.10.012. Epub 2010 Nov 23.

Characterization of the ERAD process of the L444P mutant glucocerebrosidase variant.

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Department of Cell Research and Immunology, Tel Aviv University, Ramat Aviv, 69978, Israel.


A large number of mutations in the glucocerebrosidase gene (GBA gene), encoding the lysosomal acid hydrolase glucocerebrosidase (GCase), lead to Gaucher disease (GD). The second most prevalent GD causing mutation, carried by 38% of non-Jewish patients, is L444P, resulting from a T to C transition in nucleotide 6092 of the GBA gene. It is a severe mutation that, in homozygosity, leads to neuropathic type 3 GD. We have previously shown that mutant GCase variants present variable degrees of endoplasmic reticulum (ER) retention and undergo ER associated degradation (ERAD). However, ERAD of the L444P mutant variant of GCase has never been tested. In the current study, we present results indicating that the L444P mutant protein undergoes extensive ERAD. In skin fibroblasts, originated from GD patients homozygous for L444P mutation, the level of GCase is 12%-21% of normal and at least 50% of it is in the ER. The mutant protein undergoes polyubiquitination and proteasome-dependent degradation. Recently Ambroxol, a known expectorant, was identified as a pharmacological chaperone for mutant GCase. We tested the effect of Ambroxol on the L444P mutant GCase and found that it enhances the removal of the mutant enzyme from the ER. In some cases, this removal leads to a concomitant increase in enzymatic activity.

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