The goal of this project is to characterize the genetic abnormality responsible for giant axonal neuropathy (GAN), a degenerative disorder of the peripheral nerves which typically presents in early childhood and progresses to death, usually by late adolescence. Many reported cases are offspring of consanguineous marriages, implying inheritance as an autosomal recessive trait. In addition to giant disorganized neurofilamentous swellings in nerve, disorganization of other members of the intermediate filament family of proteins is seen in other tissues; this implies that the fundamental defect is one of intermediate filament function with neurofilaments predominantly affected. By studying families affected by GAN, we plan to map and characterize the gene responsible. We propose to perform a genome-wide search, using highly polymorphic DNA markers in consanguineous families, for areas of the genome homozygous by descent; such areas have a greater increased likelihood of harboring the gene. This strategy, termed homozygosity mapping, allows mapping of recessive disorders with relatively few affected kindreds. Once the gene locus is determined, physical and fine linkage mapping will be performed; ultimately, the gene will be identified by one of a number of techniques. Although GAN is a rare illness, it is likely the characterization of the gene and its product will shed light on very basic cytoskeletal processes. Such information may lead to new theoretical and experimental strategies for other illnesses, such as amyotrophic lateral sclerosis, which have a striking neurofilamentous pathology.
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