1) Genetic basis of lysosomal storage disorders

The lysosomal storage disorders are a group of inherited diseases due to mutations in genes, which code for lysosomal enzymes. It results in the accumulation of different substrate in the lysosomes. Most of the lysosomal storage disorders present with hepatosplenomegaly, skeletal abnormalities and dysfunction of the central nervous system. Our work focused on the identification and characterization of the molecular defects in the genes responsible for these diseases and, more recently, in the development of therapeutic approaches. The analysis includes expression of mutant alleles at the RNA and protein levels. In particular, abnormal splicing, nonsense mediated RNA decay (NMD), enzyme activity and altered intracellular mutant protein trafficking are studied. At present, we are developing cellular models by RNA interference and the generation of iPS cells. The therapeutic strategies are based on the use of siRNAs and shRNAs, chaperones, aminoglycoside antibiotics and antisense oligonunucleotides, depending on the type of mutation to be treated. Our work started in 1992 with the molecular analysis of Gaucher disease and it was extended to other lysosomal diseases such Sanfilippo A, B and C syndrome, GM1 gangliosidosis/Morquio B, Maroteaux-Lamy syndrome, multiple sulfatase deficiency, Niemann-Pick type A/B and C and Krabbe disease.


Staff
Dr. Daniel Grinberg
Dr. Lluïsa Vilageliu


Predocs
Isaac Canals
Marta Gómez
Jenny Serra


Maste studentsr
Alexandre Hoffmann


Technician
Mònica Cozar


Collaborators
Dr. Helen Michelakakis (Institute of Child Health, Athens, Greece)
Dr. Gregory Pastores (NYU Medical Center, Nova York, USA)
Dr. Mariana Blanco (Laboratorio Dr. N.A. Chamoles, Buenos Aires, Argentina)
Dr. Sílvia Atrian (Dept. de Genètica, Universitat de Barcelona)
Dr. Maria Josep Coll (Institut de Bioquímica Clínica, Barcelona)
Dr. Mercè Pineda (Hospital Sant Joan de Déu, Barcelona)
Dr. Josefina Casas (CSIC, Barcelona)
Dr. Magdalena Ugarte (Universidad Autónoma de Madrid)
Dr. Francisca Sánchez (Universidad de Málaga)

2) Exome sequencing in the “Opitz C-trigonocephaly syndrome” (OCTS)

The Opitz C trigonocephaly syndrome (OCTS) is a multiple congenital anomaly syndrome characterized by trigonocephaly, mental retardation, a typical facial appearance, redundant skin, joint and limb abnormalities, and visceral anomalies. Several facts support an autosomal recessive inheritance: normal chromosomes in most patients, unaffected parents with multiaffected offspring, equal sex ratio of affected individuals, and consanguineous matings. However, dominant forms may also exist. Molecular alterations in the CD96 gene have been identified in a few cases, indicating the presence of genetic heterogeneity. We attempt to look for other Opitz C gene/s by exome sequencing of 10 unrelated patients. Exome sequencing is a new alternative to identify genes in monogenic disorders when there is no clue on the gene function and when large families are not available for linkage analysis. Targeted exome sequencing involves the capture and inspection of all protein-coding subsequences of the genome. Recent publications have demonstrated its utility in the identification of causative mutations for mendelian disorders.