The Periodic paralyses are dramatic neurological disorders which present as episodic paralysis of most muscle groups of a patient. The paralysis can last from minutes to days. The primary periodic paralyses are genetic disorders which are inherited as autosomal dominant traits. We present convincing preliminary genetic and electrophysiologic evidence that strongly suggests that hyperkalemic periodic paralysis is the result of dominant mutations of the adult skeletal muscle sodium channel alpha-subunit gene, a gene which we have cloned and then mapped to the long arm of human chromosome 17. In this proposal three laboratories have combined their expertise to elucidate the genetic, molecular genetic and electrophysiologic basis for hyperkalemic periodic paralysis. Specifically, we have shown tight linkage between the disease and the sodium channel gene in one extended family (multipoint LOD - 7.02; theta - 0). In addition, electrophysiologic patch-clamp studies of muscle cells from this family have shown specific gating abnormalities of the adult skeletal muscle sodium channel corresponding to the cloned gene. The goal of the research is to test the hypotheses that hyperkalemic periodic paralysis is a genetically homogeneous disorder, that it is caused by mutations of the adult skeletal muscle sodium channel alpha-subunit, and that the molecular genetic abnormalities of the sodium channel gene can be correlated with electrophysiological 'changes of the channel in patient muscle membranes. The proposed research project is a tightly intertwined study divided between laboratories specialized in the molecular biology of neuromuscular disease (Eric Hoffman, PhD), the clinical aspects and cell ,culture of neuromuscular disease (Robert Brown, MD PhD), and the electrophysiology of sodium channels (David Corey, PhD; Stephen Cannon, MD PhD). The proposed research is designed to provide a complete understanding of hyperkalemic periodic paralysis at the molecular level. Identification of both the amino-acid changes of the sodium channel causing paralysis in these patients and the electrophysiologic consequences of these protein abnormalities will give insight into the regulation and function of the skeletal muscle sodium channel in both health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034913-07
Application #
2685725
Study Section
Special Emphasis Panel (ZRG2-PHY (02))
Program Officer
Nichols, Paul L
Project Start
1995-05-01
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
2000-03-31
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213