A single nucleotide difference that alters splicing patterns distinguishesthe SMA gene SMN1 from the copy gene SMN2

Spinal muscular atrophy (SMA) is a recessive disorder characterized by loss of motor neurons in the spinal cord. It is caused by mutations in the telo meric survival motor neuron 1 (SMN1) gene. Alterations within an almost ide ntical copy gene, the centromeric survival motor neuron 2 (SMN2) gene produ ce no known phenotypic effect. The exons of the two genes differ by just tw o nucleotides, neither of which alters the encoded amino acids. At the geno mic level, only five nucleotides that differentiate the two genes from one another have been reported. The entire genomic sequence of the two genes ha s not been determined. Thus, differences which might explain why SMN1 is th e SMA gene are not readily apparent. In this study, we have completely sequ enced and compared genomic clones containing the SMN genes. The two genes s how striking similarity, with the homology being unprecedented between two different yet functional genes. The only critical difference in an similar to 32 kb region between the two SMN genes is the C-->T base change 6 bp ins ide exon 7. This alteration but not other variations in the SMN genes affec ts the splicing pattern of the genes, The majority of the transcript from t he SMN1 locus is full length, whereas the majority of the transcript produc ed by the SMN2 locus lacks exon 7. We suggest that the exon 7 nucleotide ch ange affects the activity of an exon splice enhancer. In SMA patients, the loss of SMN1 but the presence of SMN2 results in low levels of full-length SMN transcript and therefore low SMN protein levels which causes SMA.