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Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development.

ABSTRACT: Spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide that is characterized by loss of spinal motor neurons leading to muscle weakness and atrophy. SMA results from the loss of survival motor neuron 1 (SMN1) gene but retention of its paralog SMN2. The copy numbers of SMN1 and SMN2 are variable within the human population with SMN2 copy number inversely correlating with SMA severity. Current therapeutic options for SMA focus on increasing SMN2 expression and alternative splicing so as to increase the amount of SMN protein. Recent work has demonstrated that not all SMN2, or SMN1, genes are equivalent and there is a high degree of genomic heterogeneity with respect to the SMN genes. Because SMA is now an actionable disease with SMN2 being the primary target, it is imperative to have a comprehensive understanding of this genomic heterogeneity with respect to hybrid SMN1-SMN2 genes generated by gene conversion events as well as partial deletions of the SMN genes. This review will describe this genetic heterogeneity in SMA and its impact on disease phenotype as well as therapeutic efficacy.

SUBMITTER: Butchbach MER

PROVIDER: S-EPMC8348669 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The motor neuron response to SMN1 deficiency in spinal muscular atrophy.

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Genetic circuitry of Survival motor neuron, the gene underlying spinal muscular atrophy.

Project description:The clinical severity of the neurodegenerative disorder spinal muscular atrophy (SMA) is dependent on the levels of functional Survival Motor Neuron (SMN) protein. Consequently, current strategies for developing treatments for SMA generally focus on augmenting SMN levels. To identify additional potential therapeutic avenues and achieve a greater understanding of SMN, we applied in vivo, in vitro, and in silico approaches to identify genetic and biochemical interactors of the Drosophila SMN homolog. We identified more than 300 candidate genes that alter an Smn-dependent phenotype in vivo. Integrating the results from our genetic screens, large-scale protein interaction studies, and bioinformatic analysis, we define a unique interactome for SMN that provides a knowledge base for a better understanding of SMA.

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Project description:Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families. Greater knowledge of the molecular basis of SMA pathogenesis has fuelled the development of potential therapeutic approaches, which are illustrated here. Nusinersen, a modified antisense oligonucleotide that modulates the splicing of the SMN2 mRNA transcript, is the first approved drug for all types of SMA. Moreover, the first gene therapy clinical trial using adeno-associated virus (AAV) vectors encoding SMN reported positive results in survival and motor milestones achievement. In addition, other strategies are in the pipeline, including modulation of SMN2 transcripts, neuroprotection, and targeting an increasing number of other peripheral targets, including the skeletal muscle. Based on this premise, it is reasonable to expect that therapeutic approaches aimed at treating SMA will soon be changed, and improved, in a meaningful way. We discuss the challenges with regard to the development of novel treatments for patients with SMA, and depict the current and future scenarios as the field enters into a new era of promising effective treatments.

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