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Homozygous deletion or mutation of the  survival of motor neuron 1  gene ( SMN1 ) causes spinal muscular atrophy.  SMN1  has been duplicated in humans to create  SMN2 , which produces a low level of functional SMN protein. However, most  SMN2  transcripts lack exon 7, resulting in a non-functional protein. A single nucleotide difference near the 5′ end of exon 7 largely accounts for  SMN2  exon 7 skipping, an effect that has been attributed to loss of an exonic splicing enhancer (ESE) dependent on the SR protein splicing factor ASF/SF2 or to the creation of an exonic splicing silencer (ESS) element that functions by binding of the splicing repressor hnRNP A1. Our earlier experiments favored the latter mechanism and here we provide further evidence supporting the ESS model. We demonstrate that the striking effect of hnRNP A1 depletion on  SMN2  exon 7 splicing is specific, as hnRNP A1 depletion has little or no effect on other inefficient splicing events tested, and ASF/SF2 depletion does not affect  SMN1/2  splicing. By two different methods, we find a strong and specific interaction of hnRNPA1 with  SMN2  exon 7 and only weak and equivalent interactions between ASF/SF2 and other SR proteins with the 5′ ends of  SMN1  and  SMN2  exon 7. Finally, we describe two disease-related exon-skipping mutations that create hnRNP A1 binding sites, but show that splicing can be restored only modestly or not at all by hnRNP A1 depletion. Together our results provide strong support for the idea that  SMN2  exon 7 splicing is repressed by an hnRNPA1-dependent ESS, but also indicate that creation of such elements is context-dependent.

hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing