Nature Genetics
23, 296 - 303 (1999)
doi:10.1038/15472
Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegiaJamilé Hazan1, Nùria Fonknechten1, Delphine Mavel1, Caroline Paternotte1, Delphine Samson1, François Artiguenave1, Claire-Sophie Davoine2, Corinne Cruaud1, Alexandra Dürr3, 4, 5, Patrick Wincker1, Philippe Brottier1, Laurence Cattolico1, Valérie Barbe1, Jean-Marc Burgunder6, Jean-François Prud'homme7, Alexis Brice3, 4, 5, Bertrand Fontaine2, 3, Roland Heilig1
& Jean Weissenbach11
Genoscope, Evry, France. 2
INSERM CJF9711, Faculté de Médecine Pitié-Salpêtrière, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. 3
Fédération de Neurologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. 4
INSERM U289, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. 5
Consultation de Génétique Médicale, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. 6
Neurologische Klinik und Poliklinik, Universitätsspital Bern, Bern, Switzerland. 7
Généthon, Evry, France.
Correspondence should be addressed to Jamilé Hazan jamile@genoscope.cns.frAutosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Among the four loci causing AD-HSP identified so far, the SPG4 locus at chromosome 2p21−p22 has been shown to account for 40−50% of all AD-HSP families. Using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval, we identified a candidate gene encoding a new member of the AAA protein family, which we named spastin. Sequence analysis of this gene in seven SPG4-linked pedigrees revealed several DNA modifications, including missense, nonsense and splice-site mutations. Both SPG4 and its mouse orthologue were shown to be expressed early and ubiquitously in fetal and adult tissues. The sequence homologies and putative subcellular localization of spastin suggest that this ATPase is involved in the assembly or function of nuclear protein complexes.
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