We propose to map and identify genes in disorders of the motor neuron. We will use genetic linkage analysis to identify the chromosome localization of the genes for: (1) autosomal dominant form of familial amyotrophic lateral sclerosis in those (30% - 60%) families where the gene for this disease is not linked to chromosome 21. (2) Autosomal recessive and autosomal dominant forms of pure spastic paraplegias. Our laboratory is well suited for this task as we have DNA samples from families with these disorders and have recently identified chromosome loci for the autosomal dominant and autosomal forms of amyotrophic lateral sclerosis on chromosome 21q and 2q respectively. In addition we have preliminary evidence for linkage of recessive familial spastic paraplegia to chromosome 8. We plan to identify the gene for recessive amyotrophic lateral sclerosis on chromosome 2q. We will use genetic linkage techniques to fine map this gene, then use molecular techniques to obtain a physical map of that region and then identify candidate genes for this disease. These techniques include identifying Yeast artificial chromosomes that map to this region which will be used along with a microdissected chromosome 2 library to find closely linked polymorphic markers. Once markers within a million base pairs or so of the gene are obtained, it will be possible to prepare a physical (YAC/cosmid and pulsed field) map of the region based. Potential candidate genes can then be identified and should be contained in the microdissected library or in appropriate yeast artificial chromosome clones. cDNA libraries from the spinal cord will also be screened with clones from regional genomic libraries prepared from microdissected chromosome 2 to obtain candidate genes. Candidate genes can then be tested for their relevance by linkage analysis in our recessive ALS families. Similar techniques will be used to identify genes for amyotrophic lateral sclerosis (non chromosome 21) and the spastic paraplegias. Once the location of those genes are determined, identification of these genes and their function will allow the formulation of rational treatment and or prevention of those disorders.
