A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy

SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybr id genes and a new SMN1 mutation showed a direct relationship between prese nce of disease and exon 7 skipping. We have reported previously that the ex on-skipped product SMN Delta 7 is partially defective for self association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was e ngineered and transfected into cultured cells, and their transcripts were c haracterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and suffici ent to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fu lly compensate for SMN1 and protect from SMA is due to a nucleotide exchang e (C/T) that attenuates activity of an exonic enhancer. These findings demo nstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA reta in the SMN2 allele, therapy targeted at preventing exon 7 skipping could mo dify clinical outcome.