Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis

Background-Hereditary spastic paraparesis is a genetically heterogeneous co ndition. Recently, mutations in the spastin gene were reported in families Linked to the common SPG4 locus on chromosome 2p21-22. Objectives-To study a population of patients with hereditary spastic parapa resis for mutations in the spastin gene (SPG4) on chromosome 2p21-22. Methods-DNA from 32 patients (12 from families known to be linked to SPG4) was analysed for mutations in the spastin gene by single strand conformatio nal polymorphism analysis and sequencing. All patients were also examined c linically. Results-Thirteen SPG4 mutations were identified, 11 of which are novel. The se mutations include missense, nonsense, frameshift, and splice site mutati ons, the majority of which affect the AAA cassette. We also describe a nucl eotide substitution outside this conserved region which appears to behave a s a recessive mutation. Conclusions-Recurrent mutations in the spastin gene are uncommon. This redu ces the ease of mutation detection as a part of the diagnostic work up of p atients with hereditary spastic paraparesis. Our findings have important im plications for the presumed function of spastin and schemes for mutation de tection in HSP patients.