An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN

• Published in: Human molecular genetics 2000-01, Vol.9 (2), p.259-265
• Main Authors: Lorson, C L, Androphy, E J
• Format: Article
• Language: English
• Subjects: Alternative Splicing - genetics; Base Sequence; Cyclic AMP Response Element-Binding Protein; Enhancer Elements, Genetic - genetics; Exons - genetics; Humans; Molecular Sequence Data; Muscular Atrophy, Spinal - genetics; Nerve Tissue Proteins - genetics; RNA-Binding Proteins; SMN Complex Proteins; SMN1 gene; SMN2 gene; spinal muscular atrophy; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein; Tumor Cells, Cultured
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/9.2.259

The survival motor neuron genes, SMN1 and SMN2, encode identical proteins; however, only homo- zygous loss of SMN1 correlates with the development of spinal muscular atrophy (SMA). We have previously shown that a single non-polymorphic nucleotide difference in SMN exon 7 dramatically affects SMN mRNA processing. SMN1 primarily produces a full-length RNA whereas SMN2 expresses dramatically reduced full-length RNA and abundant levels of an aberrantly spliced transcript lacking exon 7. The importance of proper exon 7 processing has been underscored by the identification of several mutations within splice sites adjacent to exon 7. Here we show that an AG-rich exonic splice enhancer (ESE) in the center of SMN exon 7 is required for inclusion of exon 7. This region functioned as an ESE in a heterologous context, supporting efficient in vitro splicing of the Drosophila double-sex gene. Finally, the protein encoded by the exon-skipping event, Delta7, was less stable than full-length SMN, providing additional evidence of why SMN2 fails to compensate for the loss of SMN1 and leads to the development of SMA.