A new study shows that the stability and oligomerization ability of mutated survival motor neuron (SMN) 1 protein may be associated with the clinical severity of spinal muscular atrophy (SMA). The research team sought to clarify factors determining the phenotypes of 6 patients with 5 intragenic SMN1 mutations by estimating the stability and oligomerization ability of the patients’ mutated SMN1 proteins.

SMN1 and SMN2, located on chromosome 5q13, are associated with SMA. The genes are nearly identical, but their interaction and different gene expression patterns may modulate the SMA patient phenotype. In fact, studies have shown that SMA clinical severity often correlates with the copy number of SMN2 genes: the most severe form of SMA is usually associated with just 1 copy of SMN2, while the least severe form typically has 4 copies or more. Thus, higher copy numbers of SMN2 might compensate for the deletion of the SMN1 gene, improving survival outcomes and maintaining motor function in some patients.

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The researchers carried out immunoprecipitation analyses that suggested that the mutated SMN1 protein completely blocked oligomerization with the SMN2 protein in their patients. The interaction between the 2 genes ultimately appears to be associated with the clinical phenotype of the disease, resulting in the SMN1 gene being considered the disease-causing gene, while SMN2 is the disease-modifying gene.

The authors wrote, “According to our series of studies with SMA patients carrying an intragenic SMN1 mutation, there are at least three determinants of clinical phenotype of the SMA patients with an intragenic SMN mutation; (1) complex formation with partner proteins bound to mutated SMN1 proteins, (2) stability of mutated SMN1 proteins in this study and (3) oligomerization ability of mutated SMN1 proteins (this study).”

The authors concluded that for patients with SMA and an intragenic SMN1 mutation, new therapeutic strategies that target these 3 determinants should be explored.


Niba ETE, Nishio H, Wijaya YOS, et al. Stability and oligomerization of mutated SMN protein determine clinical severity of spinal muscular atrophy. Genes. 2022;13(2):205. doi:10.3390/genes13020205