EXPLORING THE MAMMALIAN NEUROMUSCULAR SYSTEM BY ANALYSIS OF MUTATIONS- SPINAL MUSCULAR-ATROPHY AND MYOTONIA

Any biological structure can be studied using mutations that interfere either with its emergence or its function. We investigate spontaneous and induced mutations in the mouse that affect neuromuscular developm ent and function. The wobbler mouse (phenotype WR, genotype wr/wr) suf fers from muscular atrophy because of the degeneration of 20-40% of th e motoneurones; it is also unable to produce functional spermatozoa. A s a step towards positional cloning of the wr gene, we have mapped the locus to proximal chromosome 11, thus excluding CNTF and its receptor as candidates, and suggesting the closely-linked Rab I gene encoding a GTP-binding protein as a possibility. In the case of the adr (arrest ed development of righting response) mouse, which shows hyperexcitabil ity of mature muscle fibres due to a reduction of the 'dampening' func tion of chloride conductance at resting potential, we have shown that the defect is in the chloride channel gene adr/Clc-1 on chromosome 6. This allowed us to predict via synteny the chromosomal location of hum an Thomsen's and Becker's myotonias as close to the TCRB gene on human chromosome 7q. The combination of these approaches with gene-targetin g approaches will allow genetic analysis of the establishment and stru cture of the neuromuscular system.