Autosomal 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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We thank HSP family members and the Association Strümpell-Lorrain for participating in this study; C. Allaire for collecting family 4014; T. Maisonobe for performing the muscle biopsy; C. Caloustian, J.-P. Fiawoumo, F. Gary and D. Torchard for sequencing help; S. Cure for critical reading of the manuscript; and C. Fizames, S. Fauré, G. Gyapay, A. Lemainque, J.-L. Petit, M. Salanoubat, T. Bruls, M. Meugnier, W. Saurin, I. Richard and A. Bernot for discussions and support. The initial part of this work was funded by the Association Française contre les Myopathies.
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Human Molecular Genetics (2019)
Bulletin of Problems Biology and Medicine (2019)
European Journal of Neurology (2019)
Clinical Science (2019)
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