Spastin, a New AAA Protein, Is Altered in the Most Frequent Form of Autosomal Dominant Spastic Paraplegia

Nat Genet. 1999 Nov;23(3):296-303. doi: 10.1038/15472.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics*
  • Adenosine Triphosphatases / metabolism
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cells, Cultured
  • Cloning, Molecular
  • DNA Mutational Analysis
  • Exons / genetics
  • Expressed Sequence Tags
  • Humans
  • Introns / genetics
  • Mice
  • Mitochondria, Muscle / metabolism
  • Molecular Sequence Data
  • Mutation*
  • Oxidative Phosphorylation
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Spastic Paraplegia, Hereditary / enzymology
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / metabolism
  • Spastic Paraplegia, Hereditary / pathology
  • Spastin

Substances

  • RNA, Messenger
  • Adenosine Triphosphatases
  • Spastin
  • SPAST protein, human
  • Spast protein, mouse

Associated data

  • GENBANK/AJ246001
  • GENBANK/AJ246002
  • GENBANK/AJ246003