Human Molecular Genetics


Research Interests

Regulation of pre-mRNA processing in human diseases.

Description of Research

The research of the Human Molecular Genetics group is focused on normal and pathological pre-mRNA processing with the aim to identify novel therapeutic strategies for correction of splicing defects. We are exploring the molecular basis of splicing defects associated with coagulation deficiencies (hemophilia), cystic fibrosis, Spinal Muscular Atrophy, and Familial Dysautonomia. Our major interest is understanding how defects in non-canonical splicing regulatory elements induce aberrant processing of pre-mRNA and develop appropriate strategies for splicing correction. We recently found that precise engineering of the U1 core spliceosomal RNA particle has a therapeutic potential in pathologies associated with exon-skipping mutations. Modified variants of U1 snRNA (Exon Specific U1 snRNAs) that binds by complementarity to intronic sequences downstream the 5’ss can correct exon skipping defects caused by different types of mutations. We are exploring this novel therapeutic strategy in cellular and animal models of coagulation defects, of Spinal Muscular Atrophy and Familial Dysautonomia and understand the molecular mechanism involved. Part of the work is also dedicated to the analysis of a novel class of pri-miRNAs we have recently identified, whose hairpins present on pre-mRNA overlap with the splice site (Splice SiteOverlapping miRNA).

Research support is also provided by NIH, TELETHON Italy, MDA and AFM. Graduate Student and Postdoctoral Positions: Enquiries with CV welcome

Recent Publications

Pianigiani,G., Licastro, D., Fortugno, P., Castiglia, D., Petrovic, I., Pagani, F. 2018.Microprocessor-dependent processing of splice site overlapping microRNA exonsdoes not result in changes in alternative splicing. RNA 24, 1158-1171 PubMed link

Donadon, I., Pinotti, M., Rajkowska, K., Pianigiani, G., Barbon, E., Morini, E., Motaln,H., Rogelj, B., Mingozzi, F., Slaugenhaupt, S.A., Pagani, F. 2018. Exon Specific U1 snRNAs improveELP1 exon 20 definition and rescue ELP1 protein expression in a FamilialDysautonomia mouse model. Hum Mol Genet 27, 2466-2476 PubMed link

Rogalska, M.E., Tajnik, M., Licastro, D., Bussani, E., Camparini, L., Mattioli, C., Pagani, F. 2016. Therapeutic activity of modified U1 core spliceosomal particles. Nat Commun, 7, 11168. PubMed link

Tajnik, M., Rogalska, M.E., Bussani, E., Barbon, E., Balestra, D., Pinotti, M., Pagani, F. 2016. Molecular Basis and Therapeutic Strategies to Rescue Factor IX Variants That Affect Splicing and Protein Function. PLoS Genet, 12, e1006082. PubMed link

Dal Mas, A., Rogalska, M.E., Bussani, E., Pagani, F. 2015. Improvement of SMN2 Pre-mRNA Processing Mediated by Exon-Specific U1 Small Nuclear RNA. Am J Hum Genet, 96, 93-103 PubMed link

Dal Mas, A., Fortugno, P., Donadon, I., Levati, L., Castiglia, D., Pagani, F. 2015. Exon-Specific U1s Correct SPINK5 Exon 11 Skipping Caused by a Synonymous Substitution That Affects a Bi-Functional Splicing Regulatory Element. Hum Mutat, 10.1002/humu.22762 PubMed link