Disease Gene Identification

Attività scientifica

Hereditary Spastic Paraplegia (HSP)

Our group is interested in the study of HSP and in particular the SPG9 form. The ALDH18A1 gene encodes for Δ1-pyrroline-5-carboxylate synthetase (P5CS), an enzyme that catalyzes the reduction of glutamate to Δ1-pyrroline-5-carboxylate (P5C), a critical step in the de novo biosynthesis of proline, ornithine and arginine. Mutations in this gene have been associated with recessive conditions (Baumgartner et al., 2000 and 2005) and our work (Panza et al., 2016) together with those of other groups (Martinelli et al., 2012, Coutilier et al., 2015, Fischer et al., 2016, Nozaki et al., 2016), demonstrated that both dominant as well as recessive mutations can exist (SPG9A MIM601162, and SPG9B MIM616586). We are currently working on the generation and characterization of model organisms and cell lines engineered by Gene Editing technologies (CRISPR/Cas9).

Next Generation Sequencing for the identification of novel forms of Inherited Thrombocytopenia

Inherited Thrombocytopenia are a heterogeneous group of disorder characterized by the lack of circulating platelets that can be associated with other mild to severe phenotypes or to the risk of developing further diseases (e.g. Bone marrow failure, hematologic malignancies, renal failure). Although more than 30 genes are known to cause this disorder, almost 50% cases is still without a molecular diagnosis because they present a novel form not previously described. The identification of novel causative genes would improve the diagnosis, the patients management and the knowledge on thrombocytopenia and platelets. Our group is interested in applying Whole Exome Sequencing to a large cohorts of more than 100 patients affected with Inherited Thrombocytopenia but without a molecular diagnosis after receiving an extensive diagnostic workout. Through this project we contributed to the identification and characterization of novel disorders and we reached a definite molecular diagnosis in 26% cases. Moreover, we could develop a statistical framework for a case-control comparison of gene enrichment in rare alleles. At present, we are analysing Copy Number Variation on the cohort and we are carrying out functional studies to confirm the role of some novel candidate genes.

Altri membri 

Dr. Tommaso Pippucci (AOSP)

Dr.ssa Pamela Magini (AOSP)

Collaborazioni nazionali e internazionali

Prof. Mario Capecchi – University of Utah, Salt Lake City, USA – caratterizzazione di un modello murino transgenico Knock In per la forma di paraparesi spastica ereditaria SPG9.

Dr. Ekkehard Schulze – University of Freiburg, Germany – generazione e caratterizzazione di un modello KO di C.Elegans per il gene Alh13.

Prof. Vicente Rubio – University of Valencia, Spain – produzione e caratterizzazione della proteina ricombinante umana Pirrolin-5-carbossilato-sintetasi e suo coinvolgimento nella patogenesi delle paraparesi spastiche ereditarie.

Prof. Nicholas Katsanis – Duke University Medical Center, Durham, NC, USA – caratterizzazione di modelli animali (Zebrafish) knock-in e knock-out per valutare in vivo la patogenicità di varianti genetiche candidate, identificate tramite whole exome sequencing.

Dr. Grazia Mancini – Erasmus MC, Rotterdam – identificazione di un nuovo gene responsabile di microcefalia e anomalie cerebrali.

Prof. James R. Lupski –  Baylor College of MedicineHouston, TX, USA – identificazione di mutazioni nel gene ATAD3A, responsabili di sindromi neurologiche

Prof.ssa Anna Savoia (Università di Trieste)

Prof. Carlo Balduini/Dott. Alessandro Pecci (Università di Pavia)