Molecular etiopathogenesis of spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recesive hereditary disease caused by premature atrophy of motor neurons of the anterior spinal horns. With regard to the severity of the disease three types of SMA are described: SMA I, II, III. SMA is caused by mutations by the gene Survival Motor Neuron I (SMNI). Gene SMNI is on chromosome 5q13, which contains many repetitive sequences and pseudogenes. Among the pseudogenes is also gene SMN2 which differs from gene SMNI only in 6 nucleotides. The product of gene SMN1, and to a smaller extent SMN2, is protein SMN which participates in the posttranscription metabolism of mRNA of all cell types and in a not too well known way also in the metabolism of the alpha-motor neurons of the anterior spinal horns. Protein SMN has several splicing isoforms. 90% of all transcripts of the SMN1 gene is complete and fully functional. They have all 7 exons. An opposite situation is found in transcription of gene SMN2 where only 10-30% transcripts are fully functional, it contains all 7 exons. The severity of the disease depends on the presence of the amount of functional molecules of protein SMN. The most frequent mutation are deletions comprising in 93% patients exon 7 and 8 of gene SMN1. In 3-6% patients an isolated deletion of exon 7 is involved. Less frequent are point mutations (1-2 patients with SM I, 4-5% patients with SMA II and III); so far some 20 patients were identified and 20 different point mutations. Another mechanism of development of mutations in gene SMN1 is gene conversion of gene SMN1 to gene SMN2. This mechanism explains also the increase of the number of copies of SMN2.