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Human Molecular Genetics Advance Access published online on July 6, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi240
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received April 20, 2005
Revised June 29, 2005
Accepted June 29, 2005

Article

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

Idit Ron 1 and Mia Horowitz 1*

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

* To whom correspondence should be addressed.
Mia Horowitz, E-mail: horwitzm{at}post.tau.ac.il


  Abstract

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 {beta}-glucocerebrosidase gene. Some of the patients suffer from neurological symptoms (type 2 and type 3 patients) while 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 reticulium (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 that originated 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.

Keywords: Gaucher disease; glucocerebrosidase; ERAD.
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