The survival motor neuron gene is present in humans in a telomeric copy, SMN1, and several centromeric copies, SMN2. Homozygous mutation of SMN1 is associated with proximal spinal muscular atrophy (SMA), a severe motor neuron disease characterized by early childhood onset of progressive muscle weakness. To understand the functional role of SMN1 in SMA, we produced mouse lines deficient for mouse Smn and transgenic mouse lines that expressed human SMN2. Smn-/- mice died during the peri-implantation stage. In contrast, transgenic mice harbouring SMN2 in the Smn-/- background showed pathological changes in the spinal cord and skeletal muscles similar to those of SMA patients. The severity of the pathological changes in these mice correlated with the amount of SMN protein that contained the region encoded by exon 7. Our results demonstrate that SMN2 can partially compensate for lack of SMN1. The variable phenotypes of Smn-/-SMN2 mice reflect those seen in SMA patients, providing a mouse model for this disease.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord, leading to muscular paralysis with muscular atrophy. No effective treatment of this disorder is presently available. Studies of the correlation between disease severity and the amount of survival motor neuron (SMN) protein have shown an inverse relationship. We report that sodium butyrate effectively increases the amount of exon 7-containing SMN protein in SMA lymphoid cell lines by changing the alternative splicing pattern of exon 7 in the SMN2 gene. In vivo, sodium butyrate treatment of SMA-like mice resulted in increased expression of SMN protein in motor neurons of the spinal cord and resulted in significant improvement of SMA clinical symptoms. Oral administration of sodium butyrate to intercrosses of heterozygous pregnant knockout-transgenic SMA-like mice decreased the birth rate of severe types of SMA-like mice, and SMA symptoms were ameliorated for all three types of SMA-like mice. These results suggest that sodium butyrate may be an effective drug for the treatment of human SMA patients. P roximal spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of anterior horn cells of the spinal cord, leading to muscular paralysis with muscular atrophy. Clinical diagnosis of SMA is based on findings of progressive symmetric weakness and atrophy of the proximal muscles. Affected individuals usually are classified into three groups according to the age of onset and progression of the disease. Children with type I SMA are most severely affected and usually have SMA symptoms before the age of 6 months and rarely live beyond 2 years. Type II and type III SMA are milder forms and the age of onset of symptoms varies between 6 months and 17 years. SMA is one of the most common fatal autosomal recessive diseases in children with a carrier rate of 1-2% in the general population and an incidence of 1 in 10,000 newborns (1). No specific treatment is currently available for SMA patients.Two survival motor neuron (SMN) genes (SMN) are typically present on 5q13: SMN1 (also known as SMN T , SMNtel) and SMN2 (also known as SMN C , SMNcen). Loss-of-function mutations of both copies of the telomeric gene, SMN1, are correlated with the development of SMA (2-5). The nearly identical centromeric gene, SMN2, appears to modify disease severity in a dose-dependent manner, as SMN protein levels from this gene are correlated with disease severity (6, 7). However, the expressed amount of intact SMN protein from SMN2 does not provide adequate protection from SMA (8).Although SMN1 and SMN2 encode identical proteins, all three forms of proximal SMA are caused by mutation in the SMN1 gene, but not in the SMN2 gene (2-5). The differences between these highly homologous genes are in their RNA expression patterns (9-12). Most SMN2 transcripts lack exons 3, 5, or most frequently, 7, with only a small amount of full-length mRNA generated. On the other hand, the SMN1 gene...