Affected individuals with SMA have a homozygous loss of function of the survival motor neuron gene SMN1 on 5q13 but keep the modifying SMN2 gene. The most common mutation causing SMA is a homozygous deletion of the SMN1 exon 7, which can be readily detected and used as a sensitive diagnostic test.

Our findings explain the basis of defective SMN2 splicing, illustrate the fine balance between positive and negative determinants of exon identity and alternative splicing, and underscore the importance of antagonistic splicing factors and exonic elements in a disease context.

Here we show that increased expression of PSF significantly promotes inclusion of exon 7 in the SMN2 and SMN1 mRNA, whereas reduced expression of PSF promotes exon 7 skipping in various cell lines and in fibroblast cells from SMA patients. In addition, we present evidence showing that PSF interacts with the GAAGGA enhancer on exon 7.

Results showed that approximately 20% of the samples had a lower exon 7 and 8 copy number for the SMN1 and SMN2 genes combined as compared to the exon 1–6 copy number. This validation study led us to investigate the prevalence of an SMN variant lacking exons 7–8 in multiple populations.

The telomeric (SMN1) and centromeric (SMN2) copies of this gene are nearly identical and encode the same protein. The critical sequence difference between the two genes is a single nucleotide in exon 7, which is thought to be an exon splice enhancer.

Here we investigated whether cell type-specific differences in the efficiency of exon 7 splicing contribute to the vulnerability of SMA motor neurons. We show that normal motor neurons express markedly lower levels of full-length SMN mRNA from SMN2 than do …

Sep 30, 2015 · We identified the rare variant c.863G>T (r.835_*3del, p.Gly279Glufs*5) in exon 7 of SMN1 in three patients affected with type I or type II SMA. Most of the SMN1 transcripts exhibited complete...

Correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in mouse models of SMA [23, 24]. The first approved drug for SMA, Nusinersen (Spinraza™), is an antisense oligonucleotide (ASO) that promotes inclusion of SMN2 exon 7 by sequestering an inhibitory cis -element called Intronic Splicing Silencer N1 or ISS-N1 [25, 26].

In 94% of all SMA cases, this mutation involves a deletion in a segment known as exon 7. This area is located in the long arm of the chromosome 5, in the 5q13.2 region (chromosomes have two “arms”: a short one, identified by the letter “p,” and a long one, identified by the letter “q”).

Several strategies have been pursued to increase the extent of exon 7 inclusion during splicing of SMN2 (survival of motor neuron 2) transcripts, for eventual therapeutic use in spinal muscular atrophy (SMA), a genetic neuromuscular disease.