Pathogenesis (disease development)
Spinal muscular dystrophy is an autosomal recessive inherited disorder that affects the “survival motor neuron” (SMN1) gene on chromosome 5. The SMN (Survival of Motor Neuron) protein expressed by the gene is essential for the function of alpha-motoneurons (the basis of active contractions of skeletal muscle).
More than 90% are caused by Raster mutations, specifically deletions (loss of nucleobases), which result in a protein that is significantly altered in structure, rendering it non-functional. The remaining percent are primarily missense mutations (meaning-changing mutations: Point mutation that causes the incorporation of a different amino acid into the protein). In this case, the protein is more slightly altered in structure, but is also non-functional. Both are associated with degeneration of alpha-motoneurons.
1/40-1/60 of the population are carriers of the allele causative for spinal muscular atrophy (one of two corresponding genes of homologous chromosomes).
In addition to the SMN1 gene, the SMN2 gene, which differs from it only in a few nucleotides, is also present. It fulfills the same function. Irrespective of mutations in the SMN1 gene, alternative splicing occurs in 90% of cases after transcription (synthesis of RNA using DNA as a template) in the cell nucleus.
This means that the exon essential for the function of the protein (coding DNA section, which thus decides on the amino acids incorporated into the protein) 7 is cut out by the spliceosome (RNA-protein complex essential in splicing) “exon skipping” and is thus no longer part of the finished mRNA. Once again, a functionless protein is formed.
Individuals with spinal muscular atrophy therefore have no functional SMN1 protein and compensation by the SMN2 protein, which is only 10% functional, is not possible.
However, the number of SMN2 gene copies varies from person to person. In general, it can be stated that the lower the symptomatology and the milder the course, the higher the number of SMN2 genes – this is the case:
- Approximately 80% of those with SMA type 1 carry 1-2 copies of the SMN2 gene.
- Approximately 82% of those with SMA type 2 carry 3 copies of the SMN2 gene.
- About 96% of those with SMA type 3 carry 3 – 4 copies of the SMN2 gene.
Etiology (causes)
Biographical causes
- Genetic burden from parents, grandparents
- Genetic risk depending on gene polymorphisms: genes/SNPs (single nucleotide polymorphism):
- Genes: SMN1 (see above).
- SNPs: 26 possible SNPs in the SMN1 gene.
- Genetic risk depending on gene polymorphisms: genes/SNPs (single nucleotide polymorphism):
