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dc.contributor.authorRoxburgh, Richard H.
dc.contributor.authorMarquis-Nicholson, Renate
dc.contributor.authorAshton, Fern
dc.contributor.authorGeorge, Alice M.
dc.contributor.authorLea, Rodney
dc.contributor.authorEccles, David
dc.contributor.authorMossman, Stuart
dc.contributor.authorBird, Thomas
dc.contributor.authorvan Gassen, Koen L.
dc.contributor.authorKamsteeg, Erik-Jan
dc.contributor.authorLove, Donald R.
dc.date.accessioned2017-05-03T13:13:53Z
dc.date.available2017-05-03T13:13:53Z
dc.date.issued2013
dc.date.modified2014-06-17T04:50:52Z
dc.identifier.issn1432-1459
dc.identifier.doi10.1007/s00415-012-6792-z
dc.identifier.urihttp://hdl.handle.net/10072/60402
dc.description.abstractThe 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.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherSpringer Medizin
dc.publisher.placeGermany
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom1286
dc.relation.ispartofpageto1294
dc.relation.ispartofissue5
dc.relation.ispartofjournalJournal of Neurology
dc.relation.ispartofvolume260
dc.rights.retentionY
dc.subject.fieldofresearchClinical sciences
dc.subject.fieldofresearchClinical sciences not elsewhere classified
dc.subject.fieldofresearchNeurosciences
dc.subject.fieldofresearchNeurosciences not elsewhere classified
dc.subject.fieldofresearchcode3202
dc.subject.fieldofresearchcode320299
dc.subject.fieldofresearchcode3209
dc.subject.fieldofresearchcode320999
dc.titleThe p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorLea, Rodney A.
gro.griffith.authorEccles, David


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