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.
