Research Groups

Mouse Molecular Genetics

Research Interests and Description

Group Members

Research Interests

Transgenic and KO models of genes related to human diseases. Regulation of gene expression through the 3' ends of the mRNAs.

Description of Research

The research interests of the Mouse Molecular Genetics Group focus on the study of the functions of genes and proteins related to human diseases, using mouse models. In previous years, we have generated a mouse model devoid of regulated splicing in the EDA exon of the fibronectin gene and studied the role of the FN isoforms (containing or not the EDA domain) in different pathological conditions. We are now focusing our attention on a recently developed mouse model of the Crigler-Najjar Syndrome (CNSI). The disease is characterized by severe jaundice (elevated blood levels of bilirubin) since birth and a lifelong risk of bilirubin encephalopathy and death if untreated. Before the advent of phototherapy, CNSI was lethal with death by kernicterus, usually occurring before the age of 15 months. The clinical management of the disease is extremely difficult. Patients have to receive life-long phototherapy treatment (about 10-12 hours/day) with a profound impact on the quality of (social) life. The effectiveness of phototherapy reduces with age, leading to increased risk of bilirubin encephalopathy and permanent brain damage. Liver transplantation is currently the only definitive treatment available.
Mutant mice die after 5-6 days after birth due to bilirubin toxicity reproducing major features of the human syndrome. We are addressing the mechanisms at the basis of bilirubin neurotoxicity and the possible therapeutic approaches to cure the disease. We performed gene therapy and rescued the lethal phenotype by lowering plasma bilirubin levels after the introduction of the wild type Ugt1a1 gene. We are now testing different gene-therapy protocols and vectors to improve the efficiency of the therapy. In addition, we are testing pharmacological therapies and setting up the conditions for an efficient phototerapy treatment of mutant mice.
The laboratory is also interested in the mechanisms regulating gene expression through the 3’ ends of the mRNAs. We are studying the mechanisms regulating tissue-specific alternative polyadenylation of the β-adducin gene. The β-adducin gene (ADD2) gene utilizes tissue specific promoters associated to tissue specific polyadenylation sites: one promoter is used in erythroid tissues while the other one, located 50 kbp upstream, is used in brain. Interestingly, one proximal polyadenylation region is used in erythroid tissues generating a 3’ UTR of about 1-1.5 kb, while a distal one is used in brain to form a 3’ UTR of 6-7 kb, depending on the species. We have identified the main cis-acting sequences acting on the distal brain polyadenylation site. We have found a number of potential protein factors participating in polyadenylation of ADD2, among them TDP-43 and PTB, which bind to the downstream element of the brain-specific ADD2 polyadenylation site. We have also found “long” distance “enhancers” and “silencers” of polyadenylation. We are currently characterizing the trans-acting factors mediating these effects in the β-adducin pre-mRNA 3’ end processing. 

Recent Publications

Malara, A., Gruppi, C., Celesti, G., Romano, B., Laghi, L., De Marco, L., Muro, A.F., Balduini, A. 2016. Alternative splicing of Extra Domain A (EIIIA) of fibronectin is dispensable for hematopoietic homeostasis. Stem Cells In Press.

Ronzitti, G., Bortolussi, G., van Dijk, R., Collaud, F., Charles, S., Leborgne, C., Vidal, P., Martin, S., Gjata, B., Sola, M.S., van Wittenberghe, L., Vignaud, A., Veron, P., Bosma, P.J., Muro, A.F., Mingozzi, F. 2016. A translationally optimized AAV-UGT1A1 vector drives safe and long-lasting correction of Crigler-Najjar syndrome. Molecular Therapy - Methods & Clinical Development 3:16049. PubMed link

Vodret, S., Bortolussi, G., Schreuder, A.B., Jasprova, J., Vitek, L., Verkade, H.J., Muro, AF. 2015. Albumin administration prevents neurological damage and death in a mouse model of severe neonatal hyperbilirubinemia. Sci Rep 5:16203. PubMed link

Bortolussi G, Zentillin L, Vanikova J, Bockor L, Bellarosa C, Mancarella A, Vianello E, Tiribelli C, Giacca M, Vitek L, Muro AF. 2014. Life-long correction of hyperbilirubinemia with a neonatal liver-specific AAV-mediated gene transfer in a lethal mouse model of Crigler-Najjar Syndrome. Hum Gene Ther 25:844-855. PubMed link

Bortolussi, G., Baj, G., Vodret, S., Viviani, G., Bittolo, T., Muro, AF. 2014. Age-dependent pattern of cerebellar susceptibility to bilirubin neurotoxicity in vivo in mice. Dis Model Mech 7:1057-1068. Pub Med link

Porro, F., Bockor, L., De Caneva, A., Bortolussi, G., Muro, A.F. 2014. Generation of Ugt1-deficient murine liver cell lines using TALEN technology. PLoS One 9:e104816.

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