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Point mutations and a large intragenic deletion in SPG11 in complicated spastic paraplegia without thin corpus callosum
  1. Claudia Crimella (crimella.claudia{at}libero.it)
  1. Scientific Institute E. Medea, Laboratory of Molecular Biology, Italy
    1. Alessia Arnoldi (alessia.arnoldi{at}bp.lnf.it)
    1. Scientific Institute E. Medea, Laboratory of Molecular Biology, Italy
      1. Francesca Crippa (fracrippa{at}excite.it)
      1. Scientific Institute E. Medea, Laboratory of Molecular Biology, Italy
        1. Maria Luisa Mostacciuolo (mstmls{at}mail.bio.unipd.it)
        1. Dept of Biology, University of Padova, Italy
          1. Francesca Boaretto (francesca.boaretto{at}unipd.it)
          1. Dept of Biology, University of Padova, Italy
            1. Manuela Sironi (manuela.sironi{at}bp.lnf.it)
            1. Scientific Institute E. Medea Laboratory of Bioinformatics, Italy
              1. Maria Grazia D'Angelo (grazia.dangelo{at}bp.lnf.it)
              1. Scientific Institute E. Medea, Neuromuscular and Neurorehabilitation Unit, Italy
                1. Simona Manzoni (simona.manzoni{at}bp.lnf.it)
                1. Scientific Institute E. Medea, Neuromuscular and Neurorehabilitation Unit, Italy
                  1. Luigi Piccinini (luigi.piccinini{at}bp.lnf.it)
                  1. Scientific Institute E. Medea, Neuromuscular and Neurorehabilitation Unit, Italy
                    1. Anna Carla Turconi (turconi{at}bp.lnf.it)
                    1. Scientific Institute E. Medea, Neuromuscular and Neurorehabilitation Unit, Italy
                      1. Antonio Toscano (antonio.toscano{at}unime.it)
                      1. Dept. of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, Italy
                        1. Olimpia Musumeci (om471{at}yahoo.com)
                        1. Dept. of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, Italy
                          1. Sara Benedetti (benedetti.sara{at}hsr.it)
                          1. Laboratory of Clinical Molecular Biology, Diagnostica e Ricerca San Raffaele, Italy
                            1. Raffaella Fazio (fazio.raffaella{at}hsr.it)
                            1. Dept. of Neurology, and Institute of Experimental Neurology (INSpe), San Raffaele Scientific Instit, Italy
                              1. Nereo Bresolin (nereo.bresolin{at}bp.lnf.it)
                              1. Dino Ferrari Centre, IRCCS Ospedale Maggiore Policlinico, Dept of neurological sciences Univ of Mila, Italy
                                1. Andrea Daga (daga{at}unipd.it)
                                1. Dulbecco Telethon Institute at the “E Medea” Scientific Institute, Conegliano Research Center, Italy
                                  1. Andrea Martinuzzi (andrea.martinuzzi{at}cn.lnf.it)
                                  1. Scientific Institute E. Medea, Conegliano Research Center, Conegliano, Italy
                                    1. Maria Teresa Bassi (mariateresa.bassi{at}bp.lnf.it)
                                    1. Scientific Institute E. Medea, Laboratory of Molecular Biology, Italy

                                      Abstract

                                      Hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is a frequent subtype of complicated HSP clinically characterized by slowly progressive spastic paraparesis with cognitive impairment and thin corpus callosum (TCC). SPG11, the gene associated with the major locus involved, encodes spatacsin a protein of unknown function. Different types of mutations were identified in patients with complex form of HSP (cHSP) including TCC. We screened a series of 45 index patients with different types of cHSP with (n=10) and without (n=35) TCC. Ten mutations, of which five are novel, were detected in seven patients. Of importance, three out of seven mutated patients present with cHSP without TCC. Among the novel mutations identified, we characterized a large intragenic rearrangement deleting 2,6kb of the SPG11 gene. The rearrangement is due to non-allelic-homologous-recombination between Alu sequences flanking the breakpoints. These findings expand the mutation spectrum of SPG11 and suggest that SPG11 mutations may occur more frequently in familial than sporadic forms of cHSP without TCC. This helps defining further clinical and molecular criteria for a correct diagnosis of the SPG11 related form of cHSP. In addition, the intragenic deletion here detected and the mechanism involved, both provide clues to address the issue of SPG11 missing mutant alleles previously reported.

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