Integrantes

Breve descripción del grupo

Our interest is focused on Hereditary Breast and Ovarian Cancer (HBOC) that is characterized by a high genetic heterogeneity. Loss-of-function variants in at least 8 genes (BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2) have been recently reported with a significant association with breast cancer risk.

Splicing is a central process of gene expression whereby introns are excised and exons are joined sequentially.ntron removal is guided by a large number of splicing factors, ribonucleoproteins and a complex array of sequences including acceptor and donor sites, polypyrimidine tract and branch point, as well as exonic and intronic splicing enhancers and silencers that stimulate or repress exon inclusion into the mature mRNA, respectively. Consequently, all these elements are potential targets of spliceogenic variants.These alterations remain often hidden as patient RNA assays to characterize them are not available.Our main line of research aims to investigate the role of mis-splicing of breast cancer genes in HBOC. Hybrid minigenes in splicing reporter plasmid are our main tool of the laboratory. They constitute a useful technology for both, the basic knowledge of splicing regulatory mechanisms and the study of the correlation between mutation, defective splicing and disease. In fact, we have developed and patented a new splicing vector, pSAD (Splicing And Disease; patent #P201231427: “Plasmid pSAD for splicing functional assays”), where there have been constructed a complete set of Breast Cancer minigenes, including BRCA2, BRCA1, CHEK2, PALB2, ATM, RAD51C, RAD51D, TP53 and BARD1.Therefore, we can potentially assay any candidate variant in these genes to study its impact on splicing. Actually, we have already analyzed ~900 variants by minigene assays.

We have also set up a splicing-minigene facility (http://www.ibgm.med.uva.es/servicios/servicio-de-splicing-minigenes/) to study any human gene under the splicing viewpoint. In fact, we have already developed minigenes of MLH1 (Lynch syndrome), SERPINA1 (Severe Alpha-1 Antitrypsin Deficiency), COL1A1 (Osteogenesis Imperfecta), CHD7 (Charge Syndrome, Intellectual Disability), GRN (Frontotemporal Dementia), UGT1A1 (Gilbert’s and Crigler-Najjar syndromes), TRPM4 (colorectal cancer) and TP53 (Li-Fraumeni Syndrome and breast cancer susceptibility).