Disease Gene Identification

Responsabile scientifico/Coordinatore - Prof Marco Seri

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.

Membri del gruppo

Emanuele Panza

Ricercatore a tempo determinato tipo b) (senior)

Marco Seri

Professore ordinario

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)


Produzione scientifica 


  • Magini P, Marco-Marin C, Escamilla JM, Martinelli D, Dionisi Vici C, Forzano F, Seri M, Rubio V, Panza E. Clinical description of two brothers with hereditary spastic paraplegia SPG9B: functional characterization of two new mutations in the ALDH18A1 gene. Ann Clin Transl Neurol. 2019 Aug;6(8):1533-1540. doi: 10.1002/ACN3.50821.
  • Panza E, Martinelli D, Magini P, Dionisi Vici C, Seri M. Hereditary spastic paraplegia is a common phenotypic finding in ARG1 Deficiency, P5CS deficiency and HHH syndrome: three inborn errors of metabolism caused by alteration of an interconnected pathway of glutamate and urea cycle metabolism. Fontiers in Neurology 2019 Feb 22;10:131. doi: 10.3389/fneur.2019.00131. PMID: 30853934.
  • Panza E, Escamilla-Honrubia JM, Marco-Marín C, Gougeard N, De Michele G, Morra VB, Liguori R, Salviati L, Donati MA, Cusano R, Pippucci T, Ravazzolo R, Németh AH, Smithson S, Davies S, Hurst JA, Bordo D, Rubio V, Seri M. ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism. 2016 Jan;139(Pt 1):e3. doi: 10.1093/brain/awv247. Epub 2015 Aug 21
  • Magini P, Palombo F, Boito S, Lanzoni G, Mongelli P, Rizzuti T, Baccarin M, Pippucci T, Seri M, Lalatta F. Prenatal diagnosis of Simpson-Golabi-Behmel syndrome. Am J Med Genet A. 2016 Dec;170(12):3258-3264. doi: 10.1002/ajmg.a.37873. Epub 2016 Sep 9.
  • Harel T, Yoon WH, Garone C, Gu S, Coban-Akdemir Z, Eldomery MK, Posey JE, Jhangiani SN, Rosenfeld JA, Cho MT, Fox S, Withers M, Brooks SM, Chiang T, Duraine L, Erdin S, Yuan B, Shao Y, Moussallem E, Lamperti C, Donati MA, Smith JD, McLaughlin HM, Eng CM, Walkiewicz M, Xia F, Pippucci T, Magini P, Seri M, Zeviani M, Hirano M, Hunter JV, Srour M, Zanigni S, Lewis RA, Muzny DM, Lotze TE, Boerwinkle E; Baylor-Hopkins Center for Mendelian Genomics; University of Washington Center for Mendelian Genomics, Gibbs RA, Hickey SE, Graham BH, Yang Y, Buhas D, Martin DM, Potocki L, Graziano C, Bellen HJ, Lupski JR. Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes. Am J Hum Genet. 2016 Oct 6;99(4):831-845. doi: 10.1016/j.ajhg.2016.08.007. Epub 2016 Sep 15.
  • Pippucci T, Maresca A, Magini P, Cenacchi G, Donadio V, Palombo F, Papa V, Incensi A, Gasparre G, Valentino ML, Preziuso C, Pisano A, Ragno M, Liguori R, Giordano C, Tonon C, Lodi R, Parmeggiani A, Carelli V, Seri M. Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early-onset arteriopathy and cavitating leukoencephalopathy. EMBO Mol Med. 2015 Jun;7(6):848-58. doi: 10.15252/emmm.201404399.
  • Magini P, Pippucci T, Tsai IC, Coppola S, Stellacci E, Bartoletti-Stella A, Turchetti D, Graziano C, Cenacchi G, Neri I, Cordelli DM, Marchiani V, Bergamaschi R, Gasparre G, Neri G, Mazzanti L, Patrizi A, Franzoni E, Romeo G, Bordo D, Tartaglia M, Katsanis N, Seri M. A mutation in PAK3 with a dual molecular effect deregulates the RAS/MAPK pathway and drives an X-linked syndromic phenotype. Hum Mol Genet. 2014 Jul 1;23(13):3607-17. doi: 10.1093/hmg/ddu070. Epub 2014 Feb 19.
  • Faleschini M, Melazzini F, Marconi C, Giangregorio T, Pippucci T, Cigalini E, Pecci A, Bottega R, Ramenghi U, Siitonen T, Seri M, Pastore A, Savoia A, Noris P. ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia. Br J Haematol. 2018 Oct;183(2):276-288. doi: 10.1111/bjh.15531. Epub 2018 Oct 23.
  • Noris P, Marconi C, De Rocco D, Melazzini F, Pippucci T, Loffredo G, Giangregorio T, Pecci A, Seri M, Savoia A. A new form of inherited thrombocytopenia due to monoallelic loss of function mutation in the thrombopoietin gene. Br J Haematol. 2017 May 3. doi: 10.1111/bjh.14694
  • De Rocco D, Melazzini F, Marconi C, Pecci A, Bottega R, Gnan C, Palombo F, Giordano P, Coccioli MS, Glembotsky AC, Heller PG, Seri M, Savoia A, Noris P. Mutations of RUNX1 in families with inherited thrombocytopenia. Am J Hematol. 2017 Jun;92(6):E86-E88. doi: 10.1002/ajh.24703
  • Marconi C, Canobbio I, Bozzi V, Pippucci T, Simonetti G, Melazzini F, Angori S, Martinelli G, Saglio G, Torti M, Pastan I, Seri M, Pecci A. 5’UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia. Journal of Hematology & Oncology 2017 10:18; https://doi.org/10.1186/s13045-016-0382-y
  • Melazzini F, Palombo F, Balduini A, De Rocco D, Marconi C, Noris P, Gnan C, Pippucci T, Bozzi V, Faleschini M, Barozzi S, Doubek M, Di Buduo CA, Stano Kozubik K, Radova L, Loffredo G, Pospisilova S, Alfano C, Seri M, Balduini CL, Pecci A, Savoia A. Clinical and pathogenetic features of ETV6 related thrombocytopenia with predisposition to acute lymphoblastic leukemia 2016 Jun 30. 0390-6078.
  • Marconi C, Di Buduo CA, Barozzi S, Palombo F, Pardini S, Zaninetti C, Pippucci T, Noris P, Balduini A, Seri M, Pecci A (2016). SLFN14-related thrombocytopenia: identification within a large series of patients with inherited thrombocytopenia. Thrombosis and Haemostasis, ISSN: 0340-6245
  • Bottega R, Marconi C, Faleschini M, Baj G, Cagioni C, Pecci A, Pippucci T, Ramenghi U, Pardini S, Ngu L, Baronci C, Kunishima S, Balduini CL, Seri M, Savoia A, Noris P (2015). ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization. Blood, ISSN: 1528-0020