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Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis
  1. J C Lindseya,
  2. M E Lushera,
  3. C J McDermottb,
  4. K D Whitec,
  5. E Reidd,
  6. D C Rubinszteind,
  7. R Bashire,
  8. J Hazanf,
  9. P J Shawb,
  10. K M D Bushbya
  1. aHuman Molecular Genetics Unit, School of Biochemistry and Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4AA, UK, bDepartment of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK, cDepartment of Neurology, Royal Manchester Children's Hospital, Manchester, UK, dDepartment of Medical Genetics, Wellcome Trust Centre for the Study of Molecular Mechanisms in Disease, Wellcome/MRC Building, Addenbrooke's Hospital, Cambridge, UK, eDepartment of Biological Sciences, University of Durham, Durham, UK, fDepartment of Developmental Biology, King's College, London, UK
  1. Dr Bushby, kate.bushby{at}ncl.ac.uk

Abstract

BACKGROUND Hereditary spastic paraparesis is a genetically heterogeneous condition. 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 paraparesis 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 conformational polymorphism analysis and sequencing. All patients were also examined clinically.

RESULTS ThirteenSPG4 mutations were identified, 11 of which are novel. These mutations include missense, nonsense, frameshift, and splice site mutations, the majority of which affect the AAA cassette. We also describe a nucleotide substitution outside this conserved region which appears to behave as a recessive mutation.

CONCLUSIONS Recurrent mutations in the spastin gene are uncommon. This reduces the ease of mutation detection as a part of the diagnostic work up of patients with hereditary spastic paraparesis. Our findings have important implications for the presumed function of spastin and schemes for mutation detection in HSP patients.

  • spastin
  • hereditary spastic paraparesis
  • mutation
  • recessive

https://doi.org/10.1136/jmg.37.10.759

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