How paraplegin works (SPG7)

Paraplegin loss responsible for cell changes causing rare SPG7 HSP

Mutations in the SPG7 gene encoding a mitochondrial protein termed paraplegin, are responsible for a recessive form of hereditary spastic paraparesis. Only few studies have so far been performed in large groups of hereditary spastic paraplegia (HSP) patients to determine the frequency of SPG7 mutations. Here, we report the result of a mutation screening conducted in a large cohort of 135 Italian HSP patients with the identification of six novel point mutations and one large intragenic deletion.

Sequence analysis of the deletion breakpoint, together with secondary structure predictions of the deleted region, indicate that a complex rearrangement, likely caused by extensive secondary structure formation mediated by the short interspersed nuclear element (SINE) retrotransposons, is responsible for the deletion event.

Biochemical studies performed on fibroblasts from three mutant patients revealed mild and heterogeneous mitochondrial dysfunctions that would exclude a specific association of a complex I defect with the pathology at the fibroblast level. Overall, our data confirm that SPG7 point mutations are rare causes of HSP, in both sporadic and familial forms, while underlying the puzzling and intriguing aspects of histological and biochemical consequences of paraplegin loss.

SOURCE:         Hum Mutat 29(4), 522-531, 2008. © 2008 Wiley-Liss, Inc.

A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia

Alessia Arnoldi 1, Alessandra Tonelli 1§, Francesca Crippa 1, Gaetano Villani 2, Consiglia Pacelli 2, Manuela Sironi 3, Uberto Pozzoli 3, Maria Grazia D’Angelo 4, Giovanni Meola 5, Andrea Martinuzzi 6, Claudia Crimella 1, Francesca Redaelli 1, Chris Panzeri 1, Alessandra Renieri 7, Giacomo Pietro Comi 8, Anna Carla Turconi 4, Nereo Bresolin 1 8, Maria Teresa Bassi 1

1Laboratory of Molecular Biology, Scientific Institute E. Medea, Bosisio Parini, Italy

2Department of Medical Biochemistry, Biology & Physics, University of Bari, Bari, Italy

3Laboratory of Bioinformatics, Scientific Institute E. Medea, Bosisio Parini, Italy

4Neuromuscular and Neurorehabilitation Unit, Scientific Institute E. Medea, Bosisio Parini, Italy

5Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico S. Donato, Department of Neurology, University of Milan, Milan, Italy

6Scientific Institute E. Medea, Conegliano Research Center, Conegliano, Italy

7Medical Genetics, Department of Molecular Biology, University of Siena, Siena, Italy

8Dino Ferrari Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena Foundation, Department of Neurological Sciences, University of Milan, Milan, Italy