Genetic analysis of the hereditary spastic paraplegias

The Hereditary Spastic Paraplegias (HSP) comprise a group of neurodegenerative diseases characterized by progressive lower limb spasticity. This disease, with a prevalence ranging from 1 to 20 in 100,000 individuals, is currently untreatable. The neuropathological hallmark is axonal degeneration of motor neurons in the corticospinal tract. However, the mechanisms of pathogenesis underlying this neurodegeneration remain poorly understood. Over the last decade, genetic studies of HSP have identified 33 loci including 14 genes. The main objective of this dissertation was to identify and characterize genes in a large North American HSP cohort. Mutation analysis of the two most common genes implicated in HSP, SPG3 and SPG4, led to the detection of nine novel mutations, including an ancestral SPG4 mutation in five French Canadian families. This screen also allowed for the molecular characterization of the p.del436N mutation in SPG3, which suggests a previously unidentified dominant-negative mechanism. Furthermore, a novel deletion in the VPS9 domain of the ALS2 gene was identified in a family with severe infantile onset HSP. In addition, linkage analysis and whole genome scan efforts resulted in the successful mapping of two novel HSP loci, SPG27 and SAX1. SAX1 represents the first locus for autosomal dominant spastic ataxia, a complicated form of HSP, with a common ancestor in Newfoundland. Finally, a positional candidate gene strategy at the SPG8 locus identified three missense mutations in a novel gene encoding strumpellin. Two mutations failed to rescue an axonal phenotype induced by morpholino knock-down of the SPG8 gene in zebrafish. Our efforts to identify and characterize HSP genes determined the underlying genetic cause in 36% of our cohort. These genetic causes include two novel loci and a novel gene. The findings are a major contribution to the characterization of the pathophysiology of HSP and significantly broaden the knowledge in the field of motor neuron disease. Analysis of the 15 known HSP genes suggests a common disease mechanism involving disrupted axonal membrane protein trafficking. Unraveling this mechanism will elucidate the functional maintenance of neurons in the corticospinal tract and will facilitate the development of therapies for HSP and related diseases.

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