The goals of the Cecil B. Day Neuromuscular Research are to (1) understand the molecular basis of inherited neuromuscular diseases and (2) investigate ways in which insights into the molecular biology of muscle disease may be used to devise treatments for these diseases. Disorders currently under investigation include distal muscular dystrophy, amyotrophic lateral sclerosis (ALS), periodic paralysis and a type of peripheral neuropathy. Several projects are on-going within the laboratory.
(1) With Dr. K. Bejaoui in the laboratory, we have established a multinational collaborative study of a rare form of muscular dystrophy characterized by adult onset, recessive inheritance, and marked wasting of distal leg muscles. Through this group, a locus for the disease gene has been defined on chromosome 2p. Studies are now underway to narrow the locus so that we can search for candidate muscle genes within the linked region.
(2) With investigators in the Neurogenetics Laboratory at the M.G.H. and at M.I.T., we are using genetic linkage analysis to study inherited forms of ALS. We and others have identified mutations an enzyme (cytosolic superoxide dismutase [SOD1]) which underly ALS in some families. We are currently studying the biological basis for motor neuron degeneration in these families using biochemical analyses of neural tissue from affected individuals. We are also studying a mouse model of the disease in mice over-expressing mutant SOD1 transgenes. In parallel studies we are looking for other gene defects in familial ALS not associated with SOD1 mutations. In one large family with recessively inherited ALS, a chromosomal locus has been defined on chromosome 2q.
(3) With Dr. S. Cannon and J. Gusella, we are investigating mutations which cause three diseases of muscle membrane excitability: hyperkalemic paralysis, myotonia congenita, and hypokalemic periodic paralysis. We and others have defined several mutations in genes encoding three ion channels whose defects underly these diseases. Respectively, these are skeletal muscle sodium, chloride and calcium channels. With Drs. L. Hayward and S. Cannon, we are using site directed channel mutagenesis and patch clamping to investigate the mechanism whereby dysfunction of the sodium and calcium channels are sensitive to levels of extracellular potassium ions and ambient temperature.
(4) Dr. A. Neumeyer in the laboratory is studying the molecular basis for myoblast fusion to form myotubes as part of a program to identify pharmacologic treatments which will augment muscle regeneration. Her efforts have focused both on families of surface molecules which interact to promote cell-cell adherence and fusion, and on protein trophic substances which alter both the levels of these molecules and the capacity for myoblast fusion and subsequent events in myogenesis.