An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: Further evidence for SMN as the primary SMA-determining gene

The gene for autosomal recessive spinal muscular atrophy (SMA) has been mapped to 5q12 in a region that contains repeated markers and genes. Three cDNAs that detect deletions in SMA patients have been reported, One of these, the survival motor neuron (SMN) cDNA, is encoded by two genes (SMN(T) and SMN(C)) which are distinguished by base changes in exons 7 and 8. Exon 7 of the SMN(T) gene is not detectable in similar to 95% of SMA cases, due either to deletion or sequence conversion, There is limited information on the mutations in SMA patients that have detectable SMN(T): these are critical for confirmation of SMN(T) as the SMA gene, Using SSCP analysis of the SMN exons we screened our SMA patients that possess at least one intact SMN(T) allele for mutations in SMN(T). We identified one type I SMA patient with an 11 bp duplication in exon 6 which causes a frameshift and premature termination of the deduced SMN(T) protein. Dosage and SSCP analysis of SMN(T) in this family indicated that the father contributed a SMN(T)-deleted allele to the affected child whereas the mother passed on the 11 bp exon 6 duplication SMN(T) allele, Analysis of RNA by RT-PCR conclusively demonstrated that the 11 bp duplication is associated with the SMN(T) locus and not SMN(C), This mutation provides strong support for SMN as the SMA-determining gene and indicates that disruption of SMN(T) on its own is sufficient to produce a severe type I SMA phenotype.