The lysosomal storage disorders are a group of inherited diseases due to mutations in genes, which code for lysosomal enzymes. The enzymatic defect causes the accumulation of different substrates. Our work started in 1992 with the molecular analysis of Gaucher disease. It included the identification of mutations in the glucocerebrosidase and Prosaposin genes, the establishment of a genotype-phenotype correlations, the fine mapping of the two genes, the study of the mechanisms underlying the Rec alleles, the analysis of the origin of the N370S mutation, the expression and characterization of mutant alleles, the study of mutations affecting splicing, trafficking, protein structure and nonsense mediated decay, and the search for new therapeutic approaches. More recently we expanded our work to perform similar studies on Sanfilippo A and B syndrome, GM1 gangliosidosis/Morquio B, Maroteaux-Lamy syndrome, multiple sulfatase deficiency, Niemann-Pick type A/B and C and Costello syndrome.

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


Predocs
Gessamí Sánchez
Laura Rodríguez
Isaac Canals


Technician
Mònica Cozar


Collaborators
Dr. Amparo Chabás (Institut de Bioquímica Clínica, Barcelona)
Dr. Gregory Pastores (NYU Medical Center, New York, USA)
Dr. Sílvia Atrian (Dept. Genètica, Universitat de Barcelona)
Dr. María Josep Coll (Institut de Bioquímica Clínica, Barcelona)
Dr. Mercè Pineda (Hospital Sant Joan de Déu, Barcelona)
Dr. Gemma Fabrias (CSIC, Barcelona)
Dr. Josefina Casas (CSIC, Barcelona)
Dr. Mariana Blanco (Laboratorio Dr. N.A.Chamoles, Buenos Aires, Argentina)
Dr. Magdalena Ugarte (Universidad Autónoma de Madrid)
Dr. Francisca Sánchez (Universidad de Málaga)



2) Genetic basis of osteoporosis and other bone phenotypes

Loss of bone mineral density (BMD) and defects in bone microarchitecture are the underlying cause of osteoporotic fracture. Twin and family studies indicate that genetic factors explain an important fraction of the variability in BMD. A cohort of 900 Spanish postmenopausal women was established. BMD values and DNA samples were collected from all the participants. The COL1A1 and CYP19 genes, encoding the ?1 subunit of type I collagen and the aromatase enzyme, respectively, were assayed as candidate genes for osteoporosis, both from a functional perspective and by means of association analyses. Other polymorphisms of different genes —VDR, ESR1, TGFb, LRP5 i LRP6 — have been also analyzed within the European Commission funded project GENOMOS. Recently, we have performed the global analysis of two genes (LRP5 and OPG) through the genotyping of a large number of relevant SNPs . We are currently analyzing polymorphisms of otherr candidate genes and performing functional studies of the polymorphisms found to be associated with the pathology. Recently, we have also started the analysis of the genetic bases of monogenic bone phenotypes (pathologic or not) such as high bone mass or hereditary multiple exostoses.

Homocysteine, a non-proteinogenic amino acid, is the product of methionine demethylation. Excess plasma homocysteine is associated with disease. Very high hyperhomocysteinaemia with homocystinuria is a rare autosomal recessive condition mainly due to defects in the CBS gene. We have analysed over 60 homocystinuric patients from Spain, Portugal, Argentina and Colombia for mutations in the CBS gene. A very prevalent mutation was identified, T191M, which accounts for over 50% of the mutant alleles, and its possible single origin was investigated. UWe have also identified several novel mutations and performed functional analyses to show their pathogenicity. Moderate hyperhomocysteinaemia, an independent risk factor for vascular disease, has a strong genetic component. Ten polymorphisms in five candidate genes (CBS, MTHFR, MTRR, MTR and GCPII) were investigated for association with cardiovascular disease. We are currently analyzing new patients with classical homocystinuria, due to mutations in the CBS gene, and we have also analyzed five patients with homocystinuria due to mutations in the MTHFR gene, a rare form of the disease.