title: Alternative splicing in spinal muscular atrophy underscores the role of an intron definition model.
abstract: Humans have two nearly identical copies of the Survival Motor Neuron (SMN) gene: SMN1 and SMN2. The two SMN genes code for identical proteins; however, SMN2 predominantly generates a shorter transcript due to skipping of exon 7, the last coding exon. Skipping of SMN2 exon 7 leads to production of a truncated SMN protein that is highly unstable. The inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), the second most prevalent genetic cause of infant mortality. Since SMN2 is almost universally present in SMA patients, correction of SMN2 exon 7 splicing holds the promise for cure. Consistently, SMN2 exon 7 splicing has emerged as one of the best studied splicing systems in humans. The vast amount of recent literature provides a clue that SMN2 exon 7 splicing is regulated by an intron definition mechanism, which does not require cross-exon communication as prerequisite for exon inclusion. Our conclusion is based on the prominent role of intronic cis-elements, some of them have emerged as the frontrunners among potential therapeutic targets of SMA. Further, the widely expressed T-cell-restricted intracellular antigen-1 (TIA1), a member of the Q-rich domain containing RNA-binding proteins, has recently been found to regulate SMN exon 7 splicing by binding to intron 7 sequences away from the 5′ ss. These findings make a strong argument for an "intron definition model", according to which regulatory sequences within a downstream intron are capable of enforcing exon inclusion even in the absence of a defined upstream 3′ ss of an alternatively spliced exon.
authors.affiliation: Department of Biomedical Sciences Iowa State University, Ames, IA, USA.
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Singh
authors.forename: Ravindra N
authors.initials: RN
authors.lastname: Singh
mesh_terms: D017398:Alternative Splicing; D005091:Exons; D006801:Humans; D007438:Introns; D008957:Models, Genetic; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D039102:Poly(A)-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000074019:T-Cell Intracellular Antigen-1
chemical_list: D039102:Poly(A)-Binding Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human