Search

Spinal muscular atrophy (SMA) is a recessive disorder characterized by loss of motor neurons in the spinal cord. It is caused by mutations in the telomeric survival motor neuron 1 (SMN1) gene. Alterations within an almost identical copy gene, the centromeric survival motor neuron 2 (SMN2) gene produce no known phenotypic effect. The exons of the two genes differ by just two nucleotides, neither of which alters the encoded amino acids. At the genomic level, only five nucleotides that differentiate the two genes from one another have been reported. The entire genomic sequence of the two genes has not been determined. Thus, differences which might explain why SMN1 is the SMA gene are not readily apparent. In this study, we have completely sequenced and compared genomic clones containing the SMN genes. The two genes show striking similarity, with the homology being unprecedented between two different yet functional genes. The only critical difference in an ~32 kb region between the two SMN genes is the C-->T base change 6 bp inside exon 7. This alteration but not other variations in the SMN genes affects the splicing pattern of the genes. The majority of the transcript from the SMN1 locus is full length, whereas the majority of the transcript produced by the SMN2 locus lacks exon 7. We suggest that the exon 7 nucleotide change affects the activity of an exon splice enhancer. In SMA patients, the loss of SMN1 but the presence of SMN2 results in low levels of full-length SMN transcript and therefore low SMN protein levels which causes SMA. [ABSTRACT FROM AUTHOR]

Discusses the development of animal models of proximal spinal muscular atrophy (SMA). SMA mice that present with symptoms similar to those seen in SMA patients; Understanding of the molecular basis of the disease; Feasibility of using the intact SMN2 gene, found in all SMA patients, as a means of treating the disorder.

Examines proximal spinal muscular atrophy (SMA), using a mice genetic model. Defects in the telometric survival motor neuron gene linked to the disease; Characteristics of a transgenic mice used to understand SMA; Insights obtained on the treatment of SMA.