Abstract
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.
Similar content being viewed by others
References
Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, De Michele G, Filla A, Cocozza S, Marconi R, Dürr A, Fontaine B, Ballabio A (1998) Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93(6):973–983
McDermott CJ, Dayaratne RK, Tomkins J, Lusher ME, Lindsey JC, Johnson MA, Casari G, Turnbull DM, Bushby K, Shaw PJ (2001) Paraplegin gene analysis in hereditary spastic paraparesis (HSP) pedigrees in northeast England. Neurology 56(4):467–471
Wilkinson PA, Crosby AH, Turner C, Bradley LJ, Ginsberg L, Wood NW, Schapira AH, Warner TT (2004) A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia. Brain 127(5):973–980. [Erratum in 127(9):2148]
Elleuch N, Depienne C, Benomar A, Hernandez AM, Ferrer X, Fontaine B, Grid D, Tallaksen CM, Zemmouri R, Stevanin G, Durr A, Brice A (2006) Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia. Neurology 66(5):654–659
Brugman F, Scheffer H, Wokke JH, Nillesen WM, de Visser M, Aronica E, Veldink JH, van den Berg LH (2008) Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes. Neurology 71(19):1500–1505
Arnoldi A, Tonelli A, Crippa F, Villani G, Pacelli C, Sironi M, Pozzoli U, D’Angelo MG, Meola G, Martinuzzi A, Crimella C, Redaelli F, Panzeri C, Renieri A, Comi GP, Turconi AC, Bresolin N, Bassi MT (2008) A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Hum Mutat 29(4):522–531
Bonn F, Pantakani K, Shoukier M, Langer T, Mannan AU (2010) Functional evaluation of paraplegin mutations by a yeast complementation assay. Hum Mutat 31(5):617–621
Schlipf NA, Schüle R, Klimpe S, Karle KN, Synofzik M, Schicks J, Riess O, Schöls L, Bauer P (2011) Amplicon-based high-throughput pooled sequencing identifies mutations in CYP7B1 and SPG7 in sporadic spastic paraplegia patients. Clin Genet 80(2):148–160
Sánchez-Ferrero E, Coto E, Beetz C, Gámez J, Corao A, Díaz M, Esteban J, Del Castillo E, Moris G, Infante J, Menéndez M, Pascual–Pascual S, López de Munaín A, Garcia-Barcina M, Alvarez V (2012) SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V. Clin Genet (in press)
Lee MH, Durnford SJ, Crowley JS, Rupert AH (1997) Visual vestibular interaction in the dynamic visual acuity test during voluntary head rotation. Aviat Space Environ Med 68(2):111–117
Weber KP, Aw ST, Todd MJ, McGarvie LA, Curthoys IS, Halmagyi GM (2008) Head impulse test in unilateral vestibular loss: vestibulo-ocular reflex and catch-up saccades. Neurology 70(6):454–463
Hudson M, Ahuriri-Driscoll A, Lea MG, Lea RA (2007) Whakapapa—a foundation for genetic research? Bioethical Enq 4:43–49
International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437(7063):1299–1320
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265
John Wilson (2009) History—Māori arrival and settlement in Te Ara—the Encyclopedia of New Zealand. http://www.TeAra.govt.nz/en/history/1
Statistics New Zealand (2006). ‘Profile of New Zealander Responses, Ethnicity Question: 2006 Census’, http://www.stats.govt.nz
Jock Phillips (2009) History of immigration-The great migration: 1871 to 1885 in Te Ara—the Encyclopedia of New Zealand. http://www.TeAra.govt.nz/en/history-of-immigration/8
Shepherd DI, Summers A (1996) Prevalence of multiple sclerosis in Rochdale. J Neurol Neurosurg Psychiatry 61(4):415–417
Strupp M, Thurtell MJ, Shaikh AG, Brandt T, Zee DS, Leigh RJ (2011) Pharmacotherapy of vestibular and ocular motor disorders, including nystagmus. J Neurol 258(7):1207–1222
Szmulewicz DJ, Waterston JA, MacDougall HG, Mossman S, Chancellor AM, McLean CA, Merchant S, Patrikios P, Halmagyi GM, Storey E (2011) Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video-oculographic diagnosis. Ann N Y Acad Sci 1233:139–147
Acknowledgments
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.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Roxburgh, R.H., Marquis-Nicholson, R., Ashton, F. et al. The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry. J Neurol 260, 1286–1294 (2013). https://doi.org/10.1007/s00415-012-6792-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-012-6792-z