1) Molecular analysis of Gaucher disease

Gaucher disease (GD) is an inherited lysosomal disorder mainly due to mutations in the gene encoding glucocerebrosidase (GBA). Our work started with the identification of mutations, the establishment of genotype-phenotype correlations and the fine mapping of the glucocerebrosidase and prosaposin genes. This allowed us to settle a direct and an indirect molecular diagnosis for the disease and to establish a common origin for the most prevalent p.N370S mutation. An exhaustive study of the mechanisms underlying the generation of recombinant alleles, was also performed. Recently, some mutant alleles have been expressed in vitro and the corresponding proteins characterized. The characterization is also done at the RNA level, by analyzing abnormal splicing, or putative nonsense mediated RNA decay mechanisms. At present, our aim is to develop therapeutic strategies. In particular, one approach focuses on siRNAs as a tool for silencing genes and the other on the use of chemical chaperones.


Staff
Dr. Lluïsa Vilageliu
Dr. Daniel Grinberg
Dr. Bru Cormand


Postdocs
Raül Santamaría


Predocs
Gessamí Sánchez


Technician
Mònica Cozar


Collaborators
Dr. Amparo Chabás (Institut de Bioquímica Clínica, Barcelona)
Dr. Mariana Blanco (Laboratorio de Neuroquímica Dr. N.A. Chamoles, Buenos Aires, Argentina)
Dr. Gregory Pastores (NYU Medical Center, New York, USA)
Dra. Sílvia Atrian (Dept. Genètica, Universitat de Barcelona)
Dr. Amadeu Llebaria, Dra. Gemma Fabriàs i Dra. Josefina Casas (CSIC, Barcelona)




2) Genetic basis of other lysosomal storage disorders: Sanfilippo A, B and C syndromes, GM1 gangliosidosis/Morquio B, Maroteaux-Lamy syndrome and Niemann-Pick types A/B and C

These diseases are caused by mutations in genes which code for lysosomal enzymes causing the accumulation of different substrates in the lysosomes. Most of the lysosomal storage disorders present with organomegaly, skeletal abnormalities and dysfunction of the central nervous system. Our work focuses on the identification of the molecular defects in the genes responsible for these diseases, and the expression and characterization of mutant alleles at the RNA and protein levels. In particular, abnormal splicing, nonsense mediated RNA decay (NMD) and enzyme activity and altered intracellular mutant protein trafficking are studied. The origin of frequent mutations is analysed by construction of haplotypes for several polymorphisms. We have also started a therapeutic approach for Sanfilippo A syndrome and Niemann-Pick type C disease based on the use of small interference RNAs (siRNAs) since, nowadays, there is no effective treatment for these pathologies. We are also developing cellular models for these diseases using interference RNA.


Staff
Dr. Lluïsa Vilageliu
Dr. Daniel Grinberg
Dr. Bru Cormand


Postdocs
Raül Santamaría


Predocs
Elena Garrido
Laura Rodríguez Pascau
Isaac Canals Montferrer


Technician
Mònica Cozar


Collaborators
Dr. Amparo Chabás (Institut de Bioquímica Clínica, Barcelona)
Dr. María Josep Coll (Institut de Bioquímica Clínica, Barcelona)
Dr. Mercè Pineda (Hospital Sant Joan de Déu, Barcelona)
Dr. Sílvia Atrian (Dept. Genètica, Universitat de Barcelona)