engleski

The neurobiology of spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease of childhood and young adults characterized by a progressive denervation of skeletal muscles due to the loss of anterior horn motor neurons, and consequently symmetrical hypotonia, muscle weakness, atrophy and paralysis. Clinically, SMA has been classified into four types according to the age at onset and disease severity. The underlying genetic defect is deletion or mutation of the telomeric copy of the SMN1 gene on the chromosome 5q13. Humans posses two copies of this gene, centromeric (SMN1) and telomeric (SMN2), which differ in only 8 single nucleotide changes, two of which are in exons 7 and 8. The SMN1 gene produces majority of full length SMN (FL-SMN) proteins in healthy individuals, because SMN2 gene C to T transition at codon 280 in exon 7 causes skipping of this exon during alternative splicing of the SMN2 gene. Consequently, about 80-90% of SMN2 transcripts lack exon 7 and produce dysfunctional protein. In homozygous absence of SMN1 gene, the 10% of FL-SMN protein produced by the SMN2 gene is not sufficient to compensate for the absence of SMN1 gene and prevent the disease (SMA type 1). However, a higher number of SMN2 copies will generate more than 10% of FL-SMN protein and this will lead to less severe SMA types (SMA 2 and SMA 3). The development of animal models of SMA, particularly the delta 7 SMA mouse with hybrid rescue allele, has led to better understanding of the genetic basis and pathophysiology of SMA, as well as to continuous efforts in finding a way to increase survival motor neuron (SMN) protein levels by: 1) activation of SMN2 gene and increasing full length SMN2 transcript level, 2) modulating SMN2 splicing, 3) stabilizing SMN mRNA and SMN protein, 4) development of neurotrophic, neuroprotective and anabolic compounds and 5) stem cell and gene therapy. The new preclinical advances warrant a cautious optimism for emergence of an effective treatment in the near future.

pathophysiology ; spinal muscular atrophy ; SMN1 gene ; SMN2 gene ; SMN protein ; treatment

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