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Autosomal dominant spastic paraplegia: refined SPG8 locus and additional genetic heterogeneity
E Reid1, A M Dearlove, M L Whiteford
1Department of Medical Genetics, University of Cambridge, UK.
Objective:
To map the gene responsible for autosomal dominant pure hereditary spastic paraplegia (ADPHSP) in a large affected family.
Background:
Autosomal dominant pure hereditary spastic paraplegia (ADPHSP) is genetically heterogeneous, and loci have been mapped at chromosomes 2p (SPG4), 14q (SPG3), 15q (SPG6), and recently, in a single family, at chromosome 8q24 (SPG8).
Methods:
The authors carried out a genomewide linkage screen on a large family with ADPHSP, for which linkage to the chromosome 2, 14, and 15 loci was excluded.
Results:
Analysis of markers on chromosome 8q24 gave a peak two-point lod score of 4.49 at marker D8S1799. Analysis of recombination events in this family and in the previously published SPG8-linked family narrowed the SPG8 locus from 6.2 cM to a 3.4-cM region between markers D8S1804 and D8S1179. In another four families, linkage to all four known ADPHSP loci was excluded. The SPG8-linked family had a significantly older mean age at onset of symptoms and had significantly more wheelchair-using patients than the four linkage-excluded families.
Conclusions:
These results contain the presence of an autosomal dominant pure hereditary spastic paraplegia (ADPHSP) locus at chromosome 8q24 and strongly suggest that there are at least five ADPHSP loci. The data provide additional evidence for locus-phenotype correlations in ADPHSP.