Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia

Abstract

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 2p2-1p22 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.

Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in theSPG4 (Spastin) gene

“…A novel point mutation detected (1633G>T) leads to a missense change in the AAA cassette, substituting a polar residue (Arginine) with a non-polar (Leucine). This residue is conserved in mouse spastin and several other related proteins [Hazan et al, 1999]. The mutation generates a restriction site for BsrI, and restriction digestion revealed that it was not present in 200 control chromosomes.…”

A polymorphic Alu insertion that mediates distinct disease-associated deletions

“…10 The present study reports on the characterization of two distinct Alu insertion-associated deletions in the SPAST gene, alterations of which cause hereditary spastic paraplegia type SPG4 (OMIM 604277). 11 Haplotyping as well as detailed analysis of the sequences involved was used to trace the probable history of the corresponding alleles, and to unravel the likely mutational mechanisms. Our findings enable a better understanding of the formation and evolutionary role of Alu insertion-associated deletions.…”

A novel missense mutation (I344K) in the SPG4 gene in a Korean family with autosomal-dominant hereditary spastic paraplegia

“…Recently, Hazen et al (1999) identified the spastin (SPG4) gene, which encodes a new member of the AAA (ATPase associated with diverse cellular activities) protein family. After this discovery, more than 70 mutations of the SPG4 gene have been reported, including missense, nonsense, and splice-site mutations, as well as insertions and deletions (Bürger et al 2000;de Bantel et al 2001;Fonknechten et al 2000;Hazan et al 1999;Hentati et al 2000;Jiggins et al 2001;Lindsey et al 2000;Namekawa et al 2001;Santorelli et al 2000;Svenson et al 2001). Here, we present a novel missense (I344K) mutation in the SPG4 gene in a large Korean family with pure AD-HSP.…”