Three novel spastin (SPG4) mutations in families with autosomal dominant hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous condition, characterised principally by progressive spasticity of the lower limbs. Forty percent of autosomal dominant (AD) pedigrees show linkage to the SPG4 locus on chromosome 2, which encodes spastin, an ATPase associated with diverse cellular activities (AAA) protein. We have performed a clinical and genetic study of three AD-HSP families linked to SPG4. Sequencing revealed three novel causative mutations. Two of the mutations were located in exon 5 (a 1-base pair (bp) insertion and a 5-bp deletion), resulting in frameshift and premature termination of translation, with the predicted protein lacking the entire AAA functional domain. The 5-bp deletion was associated with a later onset and mild cerebellar features. The third mutation was a 3-bp deletion in exon 9, resulting in the loss of a highly conserved phenylalanine residue within the AAA cassette and an apparently milder phenotype. This is the first example of a deletion of an amino acid in spastin.