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Spinal Muscular Atrophy is caused by homozygous loss of  SMN1 . All patients retain at least one copy of  SMN2  which produces an identical protein but at lower levels due to a silent mutation in exon 7 which results in predominant exclusion of the exon. Therapies targeting the splicing of  SMN2  exon 7 have been in development for several years, and their efficacy has been measured using either in vitro cellular assays or in vivo small animal models such as mice. In this study we evaluated the potential for constructing a mini-pig animal model by introducing minimal changes in the endogenous porcine  Smn1  gene to maintain the native genomic structure and regulation. We found that while a  Smn2 -like mutation can be introduced in the porcine  Smn1  gene and can diminish the function of the ESE, it would not recapitulate the splicing pattern seen in human  SMN2  due to absence of a functional ISS immediately downstream of exon 7. We investigated the ISS region and show here that the porcine ISS is inactive due to disruption of a proximal hnRNP A1 binding site, while a distal hnRNP A1 binding site remains functional but is unable to maintain the functionality of the ISS as a whole.

Absence of an Intron Splicing Silencer in Porcine Smn1 Intron 7 Confers Immunity to the Exon Skipping Mutation in Human SMN2