Research supported by NS08075 during the prior granting period led to 146 publications in peer-reviewed journals. During the next granting period, NS08075 will focus on inherited human neuromuscular diseases. The long-term goal of each of the three projects included in this application is to thoroughly understand molecular pathogenesis of these diseases, So that rational and effective therapies can be designed. Project 18 (P.Chance MD, PI) is at the earliest stage of this process. Chance et al have ascertained a very large family which is sufficiently informative to establish the genetic locus responsible for a form of familial juvenile amyotrophic lateral sclerosis (JALS) distinct from those already genetically characterized. Then, Chance et al will collaborate with the Scherer (Project 2) and Barchi (Project 3) groups to examine the structural and functional consequences of the JALS mutation. Project 14 (S. Scherer MD PhD, PI), dealing with X-linked Charcot-Marie- Tooth disease (CMT-X), is at an intermediate stage. The investigators have identified the mutated gene (which encodes connexin32), and its general function (a component of gap junctions) is known, but the role of gap junctions in Schwann cell biology remains obscure. Scherer et al will use cellular and molecular techniques to clarify this issue, then collaborate with Barchi et al to explore the biophysical aspects of the defective gap junctions in CMT-X. Project 9 (R. Barchi MD PhD, PI), dealing with skeletal muscle sodium channel mutations, begins closest to this goal. Both the identity of the mutated gene and its general function (skeletal muscle action potential generation) are known. Barchi et al will use biophysical methods to determine how point mutations in various domains of this channel alter assembly and physiological properties of this channel, and thus lead to skeletal muscle dysfunction. Two cores, directed by D. Pleasure MD, will support the projects. The Cellular and Molecular Core will provide access to shared equipment and personnel for technically demanding and repetitive morphological, cell culture, and molecular procedures. The Administrative Core will help- with fiscal management, support the operations of the External and Internal Review Committees, and includes a Javits Junior Clinical Investigatorship.
