Journal of Neurology

, Volume 260, Issue 5, pp 1286–1294 | Cite as

The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry

  • Richard H. RoxburghEmail author
  • Renate Marquis-Nicholson
  • Fern Ashton
  • Alice M. George
  • Rod A. Lea
  • David Eccles
  • Stuart Mossman
  • Thomas Bird
  • Koen L. van Gassen
  • Erik-Jan Kamsteeg
  • Donald R. Love
Original Communication


The c.1529C >T change in the SPG7 gene, encoding the mutant p.Ala510Val paraplegin protein, was first described as a polymorphism in 1998. This was based on its frequency of 3 % and 4 % in two separate surveys of controls in the United Kingdom (UK) population. Subsequently, it has been found to co-segregate with disease in a number of different populations. Yeast expression studies support its having a deleterious effect. In this paper a consanguineous sibship is described in which four members who are homozygous for the p.Ala510Val variant present with a spectrum of disease. This spectrum encompasses moderately severe hereditary spastic paraparesis (HSP) with more minor ataxia in two siblings, moderately severe ataxia without spasticity in the third, and a very mild gait ataxia in the fourth. Two of the siblings also manifest vestibular failure. The remaining eight unaffected siblings are either heterozygous for the p.Ala510Val variant, or do not carry it at all. Homozygosity mapping using a high-density SNP array across the whole genome found just 11 genes (on two regions of chromosome 3) outside the SPG7 region on chromosome 16, which were homozygously shared by the affected siblings, but not shared by the unaffected siblings; none of them are likely to be causative. The weight of evidence is strongly in favour of the p.Ala510Val variant being a disease-causing mutation. We present additional data from the Auckland City Hospital neurogenetics clinic to show that the p.Ala510Val mutation is prevalent amongst HSP patients of UK extraction belying any suggestion that European p.Ala510Val haplotypes harbour a disease-causing mutation which the UK p.Ala510Val haplotypes do not. Taken together with previous findings of a carrier frequency of 3–4 % in the UK population (giving a homozygosity rate of 20–40/100,000), the data imply that the p.Ala510Val is the most common mutation causing neurogenetic disease in adults of UK ancestry, albeit the penetrance may be low or the disease caused may be mild.


Hereditary spastic paraplegia Ataxia Vestibular failure SPG7 Loss of heterozygosity 



We acknowledge the financial support of the Auckland District Health Board A+ Trust in financially supporting this work. The SPG7 genotyping performed on the University of Washington subjects was undertaken by Athena Diagnostics Inc, S.D. Batish, Laboratory Director.

Conflicts of interest

Thomas Bird receives licensing fees from Athena Diagnostics. The authors have no other conflicts of interest to declare.

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Richard H. Roxburgh
    • 1
    • 2
    Email author
  • Renate Marquis-Nicholson
    • 3
  • Fern Ashton
    • 3
  • Alice M. George
    • 3
  • Rod A. Lea
    • 4
  • David Eccles
    • 4
  • Stuart Mossman
    • 5
  • Thomas Bird
    • 6
  • Koen L. van Gassen
    • 7
  • Erik-Jan Kamsteeg
    • 7
  • Donald R. Love
    • 3
    • 8
  1. 1.Neurology DepartmentAuckland City HospitalAucklandNew Zealand
  2. 2.Centre for Brain ResearchUniversity of AucklandAucklandNew Zealand
  3. 3.Diagnostic Genetics, LabPlusAuckland City HospitalAucklandNew Zealand
  4. 4.Genomics Research CentreGriffith Health Institute, Griffith UniversityBrisbaneAustralia
  5. 5.Neurology DepartmentWellington HospitalWellingtonNew Zealand
  6. 6.Departments of Neurology and MedicineUniversity of Washington, VA Geriatric Research Education and Clinical CenterSeattleUSA
  7. 7.Department of Human GeneticsRadboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life SciencesNijmegenThe Netherlands
  8. 8.School of Biological SciencesUniversity of AucklandAucklandNew Zealand

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