Departament de Genètica 


HUMAN MOLECULAR
 GENETICS


Susana Balcells
Neus Cols
Bru Cormand
Roser Gonzàlez
Daniel Grinberg
Gemma Marfany
Lluïsa Vilageliu

DANIEL GRINBERG


contact
bio
research
publications


RESEARCH PROJECTS


1) Genetic basis of Gaucher disease and other lysosomal storage disorders

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
Isaac Canals


Master students
Marina Rigau


Technician
Mònica Cozar


Collaborators
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. Marina Szlago (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.

Staff
Dr. Daniel Grinberg
Dr. Susana Balcells

Postdocs
Dr. Roser Urreizti

Predocs
Patricia Sarrion
Behjat Gholami

Technician
Mònica Cozar

Collaborators
Dr. Adolfo Díez-Pérez (Servei de Medicina Interna, Hospital del Mar)
Dr. Leonardo Mellivobski (Servei de Medicina Interna, Hospital del Mar)
Dr. Xavier Nogués Solan (Servei de Medicina Interna, Hospital del Mar)
Dr. Roberto Elosúa (Institut Municipal d'Investigacions Mèdiques)
Dr. Stuart Ralston (University of Edimburgh, UK)
Dr. André Uitterlinden (Erasmus University Rotterdam, Holanda)
Sergi Vives Civit (Departament de Estadística, Facultat Biologia, Universitat de Barcelona).



3) Homocysteine and diesease: genetic aspects of homocystinuria and hyperhomocysteinemia

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.



Staff
Dr. Daniel Grinberg
Dr. Susana Balcells


Postdocs
Dra. Roser Urreizti


Technician
Mònica Cozar


Collaborators
Dr. Rafael Artuch (Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona)
Dr. Xavier Pintó (Unitat d'Arteriosclerosi, Centre Sanitari Universitari de Bellvitge, Barcelona)
Dr. Laura Vilarinho (Porto, Portugal)
Dr. María Luz. Couce (Santiago de Compostela)
Dr. Raquel Kremer (Córdoba, Argentina)
Dr. Jan P. Kraus (University of Colorado, Denver, CO, USA)
Dr. Sílvia Atrian (Dept. Genètica, Universitat de Barcelona)
Dr. Magdalena Ugarte (Universidad Autónoma de Madrid)
Dr. Francisca Sánchez (Universidad de Málaga)



4) 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.


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


Postdocs
Dra. Roser Urreizti


Collaborators
Dr. John M Opitz (University of Utah School of Medicine, Salt Lake City, USA)
Dr. Giovanni Neri (Universitá Cattolica del Sacro Cuore, Roma, Italy)
Carles Godall (Associació Síndrome Opitz C)