PDF file: EURASNET Annual Report 2008

Participant 7 – Francisco Barallea) Work performed during the periodWP2:SHARING RESOURCES, TECHNOLOGY AND RELIABLE PROTOCOLSFurther refinement of our minigene system for routing use indiagnostic laboratories is in progress. As described in theWP12 report at deliverable 214, the minigene system has beensupplied to several researchers in other research institutionsand an EMBOreports Viewpoint is being written up togetherwith Diana Baralle for publication in 2009.• WP4: THE ALTERNATIVE SPICING DATABASEInformation for the ASD hosted at the EBI has been provided toother bioinformatics facilities (DBASS5, DBASS3) developed by Dr.Igor Vorechovsky at the University of Southampton in collaborationwith our group.WP7:MOLECULAR CHARACTERIZATION OF SPLICING SUBSTRATESParticipant 7 has collaborated in the molecular characterization ofpatients affected with Sandhoff disease (SD) carrying splicingmutations in the HEXB gene. In addition, Baralle's group has set up asystem to determine the effect on the splicing properties of humanprotein TDP-43 carrying different mutations associated with thedevelopment of ALS/FTLD disease (objective 165). As part ofobjective 166, Ashish Dhir from this group has been visiting thelaboratory of Reinhard Lührmann twice (12-26th July, 2008 and 19thOctober-14th of November, 2008) to investigate the formation ofspliceosomal complexes that mediate the inclusion of a diseaserelatedpseudoexon in the ATM gene. Finally, functional validationshave been performed by Participant 7 regarding the variousinteractors that bind to the CFTR exon 12 CERES element, whichinclude ASF/SF2, SRp55 and hnRNP A1 (objective 167).• WP12: MIS-SPLICING AND DISEASEPID7 has continued to study several regulatory elements in the genesof interest (CFTR, NF-1, HERG, BRCA, and ATM) from the point ofview of their RNA-protein and RNA-RNA interactions. In parallel, PID7is investigating the effect of knocking down interesting proteins suchas TDP-43 a splicing factor involved in several neurodegenerativediseases. In addition, we have developed a Drosophila model ofneurodegenerative disease by knocking down TBPH, the homologueof human TDP-43. Flies lacking TBPH appear externally normal butpresent deficient loco-motor behaviors, reduced life span andanatomical defects at the neuromuscular junctions. The phenotypecan be rescued by expression of human TDP-43 in the moto-neuronsof TBPH-deficient Drosophila.WP14:CHEMICAL BIOLOGY AND THERAPEUTICSPID7 has recently characterized the exact sequence that nuclearfactor TDP-43 utilizes to bind other members of the hnRNP A/Bfamily. As previously demonstrated, the interaction of TDP-43 with143