SEARCH FOR NEW DISEASE CAUSING GENES AND GENOTYPE-PHENOTYPE CORRELATION IN HEREDITARY SPASTIC PARAPLEGIA
- 2 Years 2006/2008
- 197.000€ Total Award
Hereditary Spastic Paraplegia (HSP) represents a heterogeneous group of disorders with progressive spasticity of the legs. The disease is classified in "pure" and "complicated" forms on the basis of additional features associated with spasticity. The project we propose aims mainly to search for new HSP genes. To achieve this goal we will use different approaches. Firstly, we will try to identify the causative genes of two autosomal dominant (AD) complicated HSP forms. Through linkage studies, proponent groups have mapped these two HSP forms (SPG29 and SPG9) on chromosome 1 and 10, respectively. Taking advantage of the results of the Human Genome Project, the complete sequence of the critical regions as well as the number of genes included are available. In the SPG29 critical region 147 transcripts are present, while in the SPG9 there are 50 transcripts. Some candidate genes have already been analyzed but they are not involved in the phenotypes. A second aim of the project is the identification through linkage analysis of new HSP loci in families with recurrence of HSP. In particular, we will study two pedigrees: one is a large Italian family presenting an AD pure form of HSP in which preliminary linkage studies seem to exclude the involvement of the ADHSP loci identified so far; a second Italian family has an ARHSP form complicated by thin corpus callosum (TCC). Homozygosity mapping of this family has excluded the linkage on chromosome 15 where a form of HSP-TCC was already mapped and has allowed us to identify other candidate regions. We have collected additional families with the same phenotype to be analyzed for the candidate regions identified. Finally, another aim of the proposal is to establish how frequently atlastin, HSP60, KIF5A, and NIPA1 mutations are responsible for causing ADHSP and whether there is a recognizable clinical phenotype for HSP caused by these mutations.