Hyperkalemic familial periodic paralysis (FPP) is an autosomal dominant muscle disease with onset in infancy or early childhood. This disorder is manifested by transient episodes of paralysis, frequently associated with elevated serum potassium levels. I have obtained a large pedigree containing 40 living individuals affected by hyperkalemic FPP. This family will form the basis for identifying markers linked to this disease. The expected optimal LOD score in this kindred is 18.6. The long term goal of this work is to characterize the gene and its product. Compelling electrophysiologic and biochemical evidence implicates altered sodium regulation as the defect in this disease. It is reasonable to assume that a mutation in a skeletal muscle sodium channel (NaCh) or Na+/K+-ATPase gene is responsible for the disease. I have obtained a human brain NaCh and several Na+/L+-ATPase genes and plan to use them as probes in a linkage study of hyperkalemic FPP. If the disease gene does not co-segregate with one of the candidate genes, a general linkage approach will be used to identify closely linked markers to the disease gene. Additionally, I have obtained a human skeletal muscle cDNA library and will screen it with a human brain NaCh and rat skeletal muscle NaCh genes to isolate additional candidate genes. The second phase of the project will depend on the method with which linkage is established. Co-segregation of a candidate gene with the disease allele will lead to characterization of that gene. If no candidates co-segregate with the disease allele, information from the general linkage will be used to construct a high resolution genetic and physical map. I've also established ties with collaborators who can provide additional pedigrees with the same, and related muscle diseases for further study. This work will lead to prenatal and presymptomatic diagnosis capability. This information may result in better understanding of this disorder, normal muscle development and muscle regulation.
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