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.

Staff
Dr. Susana Balcells
Dr. Daniel Grinberg

Postdocs
Dr. Roser Urreizti

Technician
Mònica Cozar

Collaborators
Dr. Mª Antònia Vilaseca (Hospital St. Joan de Déu, Esplugues de Llobregat, Barcelona)
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. Eva López Quesada (Hospital de Terrassa, Terrassa, Spain)
Dr. M. Rodés (Institut de Bioquímica Clínica, Barcelona)
Dr. L. Vilarinho (Porto, Portugal)
Dr. M.L. Couce (Santiago de Compostela, Spain)
Dr. Martha Bermúdez (Pontificia Universidad Javeriana, Bogotá, Colombia)
Dr. Alfonso Córdoba (Medellín, Colombia)
Dr. Raquel Kremer (Córdoba, Argentina)
Dr. Néstor Chamoles (Buenos Aires, 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)

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.