Human Molecular Genetics, 2003, Vol. 12, No. 1 71-78
© 2003 Oxford University Press
Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus
1Molecular Neurogenetics Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM), E-0223 Université d'Evry, GENOPOLE, Evry, France and 2Genoscope, Centre National de Séquençage, and CNRS UMR 8030, Evry, France
Received August 27, 2002; Accepted November 1, 2002
Mutations of spastin are responsible for the most common autosomal dominant form of hereditary spastic paraplegia (AD-HSP), a disease characterized by axonal degeneration of corticospinal tracts and posterior columns. Generation of polyclonal antibodies specific to spastin has revealed two isoforms of 75 and 80 kDa in both human and mouse tissues with a tissue-specific variability of the isoform ratio. Spastin is an abundant protein in neural tissues and immunolabeling experiments have shown that spastin is expressed in neurons but not in glial cells. These data indicate that axonal degeneration linked to spastin mutations is caused by a primary defect of neurons. Protein and transcript analyses of patients carrying either nonsense or frameshift spastin mutations revealed neither truncated protein nor mutated transcripts, providing evidence that these mutations are responsible for a loss of spastin function. Identifying agents able to induce the expression of the non-mutated spastin allele should represent an attractive therapeutic strategy in this disease.
* To whom correspondence should be addressed at: Molecular Neurogenetics Laboratory, INSERM, Université d'Evry, E-0223, GENOPOLE, 2 rue Gaston Crémieux, CP5724, 91057 Evry, France. Fax: +33 160874550; Email: j.melki{at}genopole.inserm.fr
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