Identification and characterization of the porcine (<i>Sus scrofa</i>) survival motor neuron (<i>SMN1</i>) gene: An animal model for therapeutic studies

Lorson, Monique A.; Spate, Lee D.; Prather, Randall S.; Lorson, Christian L.

doi:10.1002/dvdy.21642

Cited by 19 publications

(14 citation statements)

References 60 publications

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“…The resulting Yucatan Smn1 gene sequence has been submitted to the GenBank sequence database under accession number KF585502. Contrary to previously published data [20] , but in line with the recently published Duroc porcine genome from Ensembl (Sscrofa9), we found that porcine Smn1 is composed of not 9 exons but instead 10, and that the last two exons are located much further downstream from exon 7 than in the human SMN1 and SMN2 genes.…”

Section: Resultssupporting

confidence: 74%

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

et al. 2014

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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.

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Section: Resultssupporting

confidence: 74%

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

et al. 2014

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“…A promoter-trap strategy is advantageous as it typically decreases the number of random integration events that give rise to G418-resistant colonies, thereby decreasing the number of false positive G418-resistant colonies. Previous studies demonstrated that SMN was robustly expressed in pig fetal fibroblast cells; therefore a SMN promoter-trap strategy was possible (Lorson et al 2008). …”

Section: Resultsmentioning

confidence: 99%

“…Pig SMN co-localizes with human SMN in the cytoplasm and to nuclear gems, and transient transfection of pig SMN1 into 3813 SMA type I fibroblasts rescues the deficiencies of total SMN protein and gem formation (Lorson et al 2008). Pig SMN can also rescue deficiencies in snRNP assembly in SMA patient fibroblast extracts (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Disruption of the Survival Motor Neuron (SMN) gene in pigs using ssDNA

et al. 2011

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Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease that is a result of a deletion or mutation of the SMN1 (Survival Motor Neuron) gene. A duplicated and nearly identical copy, SMN2, serves as a disease modifier as increasing SMN2 copy number decreases the severity of the disease. Currently many therapeutic approaches for SMA are being developed. Therapeutic strategies aim to modulate splicing of SMN2-derived transcripts, increase SMN2 gene expression, increase neuroprotection of motor neurons, stabilize the SMN protein, replace the SMN1 gene and reconstitute the motor neuron population. It is our goal to develop a pig animal model of SMA for the development and testing of therapeutics and evaluation of toxicology. In the development of a SMA pig model, it was important to demonstrate that the human SMN2 gene would splice appropriately as the model would be based on the presence of the human SMN2 transgene. In this manuscript, we show splicing of the human SMN1 and SMN2 mini-genes in porcine cells is consistent with splicing in human cells, and we report the first genetic knockout of a gene responsible for a neurodegenerative disease in a large animal model using gene targeting with single-stranded DNA and somatic cell nuclear transfer.

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“…While the results from these studies have been promising, the current challenge involves confirming these findings in models using larger animals to determine whether neurones can reconnect over extended distances, as well as to ascertain the safety of the treatments. With this in mind, the pig (Sus scrofa) SMN gene has recently be identified and characterised (22).…”

Section: Discussion: Prospects and Considerations For Future Use Of Cmentioning

confidence: 99%

Childhood spinal muscular atrophy and stem cell research: Is cellular replacement therapy the answer? (Review)

O'Hare

Young²

2008

Mol Med Rep

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Abstract. Childhood spinal muscular atrophy (SMA) is an autosomal disorder caused by mutations in the survival motor neuron (SMN) gene. Although SMN is a ubiquitously expressed protein, mutations in SMN specifically cause the targeted deterioration of ·-motor neurones of the spinal cord. This results in the progressive wasting of the voluntary muscles of the limbs and trunk. Although there is currently no treatment or cure for SMA, several lines of investigation are underway. These include a) screens for small compounds that modulate disease phenotype, b) gene therapy and c) stem cell therapy. In this review, we discuss the current state of stem cell research, concentrating on recent advances and highlighting areas where more research is needed. We also discuss the implications of this research for SMA.

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Identification and characterization of the porcine (Sus scrofa) survival motor neuron (SMN1) gene: An animal model for therapeutic studies

Cited by 19 publications

References 60 publications

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

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

Disruption of the Survival Motor Neuron (SMN) gene in pigs using ssDNA

Childhood spinal muscular atrophy and stem cell research: Is cellular replacement therapy the answer? (Review)

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