Genetic Linkage Studies - AT08 AT66
Ataxia is a movement disorder characterized by poor motor coordination and a wide-based, unsteady gait. There may also be abnormalities of eye movements, dysfunction of the cerebellum and its associated systems, lesions in the spinal cord, or peripheral sensory loss. Frequently, atrophy of the cerebellum occurs. Ataxias can occur sporadically as a result of trauma or other neurodegenerative process or it can be inherited as a Mendelian trait. There are at least seventeen distinct genetic disorders that belong to the ataxia group. They are distinguished on the basis of age of onset, degree and rate of progression, and the presence or absence of other associated abnormalities. The hereditary ataxias are also categorized by mode of inheritance and causative gene or chromosomal locus. Both peripheral and/or central nervous system may be affected. In the lab we obtain blood samples from families who have consented to be tested for the genetic ataxias. DNA is obtained from the leukocytes of each family member and genotyped for alleles at polymorphic markers throughout the genome or located near candidate genes.
The location of a gene involved in an inherited disorder can be found by a process called gene mapping. There is physical mapping and genetic mapping, the former being used to assign genes depending on their location on the chromosome while the latter is the measurement of the tendency of genes to segregate together through meiosis. By looking at the genotypes and the disease and how they are transmitted from parents to offspring in the pedigree, we can get information about the location of the disease gene in the genome. We look for crossovers between the marker and the disease that may have occurred during meiosis. Once a location for the gene is known, electronic databases are searched for candidate genes, which may cause the disorder. The next step involves designing primers suitable for the Polymerase Chain Reaction (PCR). The candidate gene is amplified from the subject's genomic DNA by PCR where many copies of this gene or part of the gene are synthesized. Depending on the method the product is either radioactively or fluorescently tagged. To detect mutations the amplified sequence is read by an automated machine for the fluorescent method or an autoradiograph for the radioactivity method.
