Chronic Juvenile Amyotrophic Lateral Sclerosis (JALS) combines the features of a spinal muscular atrophy syndrome with upper motor neuron dysfunction. We have identified a large pedigree in Southern Maryland segregating an autosomal dominant gene for this form of JALS. Over 75 persons in this family are affected with a peripheral neuropathy characterized by an age of onset in adolescence with slow progression, leading to severe neuromuscular impairment by the fourth and fifth decades. Altered or abnormal expression of a motor neuron-specific component or a more widely-expressed protein whose function is crucial to motor neuron function is suspected. The gene for this disorder does not map to known regions of other motor neuron syndromes including the Familial Amyotrophic Lateral Sclerosis (ALS1) locus on chromosome 21, the Juvenile Amyotrophic Lateral Sclerosis (ALS2) locus on chromosome 2 or to the Spinal Muscle Atrophy (SMA) locus on chromosome 5. We propose to investigate the molecular basis of the JALS gene in this pedigree by techniques of positional cloning, including linkage analysis, physical map construction and analysis of transcripts and candidate genes. Experiments aimed to characterize the patterns and distribution of expression of this gene at the transcriptional and protein revels are proposed through in situ hybridization analysis, construction of transgenic animals, protein/antibody production and analysis in a motor neuron cell culture system. Genetic analysis in this large JALS pedigree affords the opportunity to identify and characterize an important motor neuron component.
