Establishment of treatment strategy for spinal muscular atrophybased on the SMN2gene transcription control

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More than 95 % of spinal muscular atrophy (SMA) patients show homozygous deletion of SMN1. SMN2, a highly homologous gene of SMN1, compensates for the SMN1deletion to some degree; copy number of SMN2is inversely correlated to the clinical severity of SMA. Although the promoter sequences of the two genes are almost identical, c.-318 GCC insertion has been identified as a specific polymorphism to the SMN1 promoter. In this study, we found c.-318 GCC insertion polymorphism in the SMN2 promoter of an SMN1-deleted SMA patient with milder phenotype than expected for low copy number of SMN2. However, transcript amount of SMN2in the white blood cells was smaller than other five SMN1-deleted SMA patients, suggesting that the polymorphism did not increase the transcriptional activity. Besides, reporter gene assay using plasmid constructs with or without c.-318 GCC insertion polymorphism demonstrated that the polymorphism had a slightly negative effect on the transcription efficiency. In conclusion,c.-318 GCC insertion polymorphism in the SMN2 promoter may not be associated with the milder phenotype of the patient, suggesting the presence of non-SMN2-related modifying factors of SMA severity. Our experimental data using plasmid constructs with or without c.-318 GCC insertion polymorphism suggested that in thecase of medical treatment for SMA, it is necessary to change the kind and quantity of the SMN2 -activating medicine by the presence of c.-318 GCC insertion polymorphism.