Spinal Muscular Atrophy: Why do low levels of SMN make motor neurons sick?

By A. Burghes, C. Beattie. Nature Reviews Neuroscience, 2009

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Many neurogenetic disorders are caused by the mutation of ubiquitously expressed genes. One such disorder, spinal muscular atrophy, is caused by loss or mutation of the survival motor neuron1 gene (SMN1), leading to reduced SMN protein levels and a selective dysfunction of motor neurons. SMN, together with partner proteins, functions in the assembly of small nuclear ribonucleoproteins (snRNPs), which are important for pre-mRNA splicing. It has also been suggested that SMN might function in the assembly of other ribonucleoprotein complexes. Two hypotheses have been proposed to explain the molecular dysfunction that gives rise to spinal muscular atrophy (SMA) and its specificity to a particular group of neurons. The first hypothesis states that the loss of SMN's well-known function in snRNP assembly causes an alteration in the splicing of a specific gene (or genes). The second hypothesis proposes that SMN is crucial for the transport of mRNA in neurons and that disruption of this function results in SMA.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e617ccacb05d00a51ed99591a9d07b3139f08f24

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Citations in the corpus

Current Clinical Applications of In Vivo Gene Therapy with AAVs (2020, background): “SMN1 is telomeric and the highly homologous SMN2, lying in a centromeric position.(1,4) An exon 7 point mutation of SMN2 gene results in exon splicing and exclusion from the final transcript, resulting in an unstable degradable protein.”
Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis (2013, neutral): “TDP-43, FUS/TLS, and SMN, a Common Pathogenic Pathway between ALS and Spinal Muscular Atrophy Spinal muscular atrophy (SMA) is a motor neuron disease caused by deficiency in the survival motor neuron (SMN) protein (reviewed in Burghes and Beattie, 2009).”