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Human Molecular Genetics Advance Access originally published online on July 6, 2005
Human Molecular Genetics 2005 14(16):2387-2398; doi:10.1093/hmg/ddi240
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity

Idit Ron and Mia Horowitz*

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

* To whom correspondence should be addressed. Tel: +972 36409285; Fax: +972 36422046; Email: horowitzm{at}post.tau.ac.il

Received April 20, 2005; Accepted June 29, 2005

Gaucher disease (GD), an autosomal recessive disease, is characterized by accumulation of glucosylceramide mainly in cells of the reticuloendothelial system, due to mutations in the acid ß-glucocerebrosidase gene. Some of the patients suffer from neurological symptoms (type 2 and type 3 patients), whereas patients with type 1 GD do not present neurological signs. The disease is heterogeneous even among patients with the same genotype, implicating that a mutation in the glucocerebrosidase gene is required to cause GD but other factors play an important role in the manifestation of the disease. Glucocerebrosidase is a lysosomal enzyme, synthesized on endoplasmic reticulum (ER)-bound polyribosomes and translocated into the ER. Following N-linked glycosylations, it is transported to the Golgi apparatus, from where it is trafficked to the lysosomes. In this study, we tested glucocerebrosidase protein levels, N-glycans processing and intracellular localization in skin fibroblasts derived from patients with GD. Our results strongly suggest that mutant glucocerebrosidase variants present variable levels of ER retention and undergo ER-associated degradation in the proteasomes. The degree of ER retention and proteasomal degradation is one of the factors that determine GD severity.


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