Research Groups

Human Molecular Genetics

Research Interests and Description

Research Interests

Regulation of pre-mRNA processing in human diseases.

Description of Research

The lab focuses on studies of normal and pathological pre-mRNA processing. We aim to evaluate the genes involved in several disorders, including Friedreich ataxia, Cystic Fibrosis, Long QT syndrome, cancer and coagulation deficiencies in order to unravel the mechanisms by which mutations affect pre mRNA processing and provide appropriate therapeutic correction strategies.
We are using biochemical and molecular approaches to study the splicing mechanisms and their regulation mediated by exonic and intronic regulatory elements. The BRCA1 exon 18 is used as a model to clarify aberrant exon skipping and to understand the relationships between the splicing regulatory elements in exon definition. On the other hand, ATM mutants in Ataxia Telangiectasia, GAA repeat expansions in Friedreich ataxia and rybozymes in model minigenes are utilized to understand the processing of large intronic sequences.
In collaboration with genetic screening laboratories, we are systematically evaluating the effect of the exonic substitutions and intronic variants in Long QT genes and Coagulation Factors in order to improve diagnosis and identify potential targets for therapeutic correction. Modified U1 snRNAs and oligonucleotides are actively tested for correction of defective 5' splice sites in coagulation deficiencies.

Recent Publications

Pastor, T., Talotti, G., Lewandowska, M.A., Pagani, F. 2009. An Alu-derived intronic splicing enahncer facilitates intronic processing and modulates aberrant splicing in ATM. Nucleic Acids Res. In press

Byrne, J.A., Strautnieks, S.S., Ihrke, G., Pagani, F., Knisely, A.S., Linton, K.J., Mieli-Vergani, G., Thompson, R.J. 2009. Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing. Hepatology 49, 553-567

Crotti, L., Lewandowska, M.A., Schwartz, P.J., Insolia, R., Pedrazzini, M., Bussani, E., Dagradi, F., George, A.L. Jr., Pagani, F. 2009. A KCNH2 branch point mutation causing aberrant splicing contributes to an explanation of genotype-negative long QT syndrome. Heart Rhythm 6, 212-218

Pinotti, M., Balestra, D., Rizzotto, L., Maestri, I., Pagani, F., Bernardi, F. 2009. Rescue of coagulation factor VII function by the U1+5A snRNA. Blood 113, 6461-6464

Pinotti, M., Rizzotto, L., Balestra, D., Lewandowska, M.A., Cavallari, N., Marchetti, G., Bernardi, F., Pagani, F. 2008. U1-snRNA-mediated rescue of mRNA processing in severe factor VII deficiency. Blood, 111, 2681-2684

Tanner, G., Glaus, E., Barthelmes, D., Ader, M., Fleischhauer, J., Pagani, F., Berger, W., Neidhardt, J. 2008. Therapeutic strategy to rescue mutation-induced exon skipping in rhodopsin by adaptation of U1 snRNA. Hum Mutat. 30, 255-263