Human MutationIN THIS ISSUE

& Understanding the Underlying Patholo-gical Mechanism of Mutations Located in 30

Splice Sites and Adjacent Exonic Regions

Many sequence variations affect the pre-mRNA splicing process.While representing only about 10% of reported mutations, somedata suggest that up to 50% of alleles causing human diseaseinfluence splicing. In the last few years, a more precise under-standing of the splicing process has revealed new therapeutic targetsand strategies that may be applied to a number of Mendeliandisorders. In this context, Doktor and colleagues (Hum Mutat32:xxx– yyy, 2011) broaden the knowledge about the molecularmechanism of splice mutation pathogenesis through a comprehen-sive study of the 30 splice site of exon 7 of the SMN1 and SMN2genes. They explore the molecular basis of exon retention andprovide a better understanding of this phenomenon, which isessential for increasing the therapeutic inclusion of exon 7 of SMN2.

The authors report that the sequence spanning the 30splice site ofSMN1/SMN2 exhibits an ESS motif similar to one detected in exon

5 of the MCAD gene, which binds hnRNP A1 protein and inhibitsexon 7 inclusion in the protein. Knock-down and pull-downexperiments using a number of mutant ESS sequences helped theauthors to elucidate the complete molecular basis of the retention ofthe exon. They propose that hnRNP A1 may function as a generalinhibitor of exon inclusion by direct binding to the 30 ss of exons,where this inhibitory ESS motif constitutes part of the 30 ss. Thisalso illustrates how the third and fourth nucleotide residues of anexon could modulate splice-site strength. Doktor et al. conclude thatgenetic variation within this region, which had been assumed to beneutral, has the potential to induce exon skipping and possiblydisease susceptibility, depending on cell type or splicing factorconcentration changes. The authors provide clues that allow a betterunderstanding of the underlying pathological mechanism of thesplicing mutations located in the 30 ss and the adjacent exonicregion of genes containing this motif.

–Belen Perez, Centro de Biologıa Molecular,Universidad Autonoma de Madrid

DOI 10.1002/humu.21453

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