Plastin 3 Is a Protective Modifier of Autosomal Recessive Spinal Muscular Atrophy

Abstract

Homozygous deletion of the survival motor neuron 1 gene (SMN1) causes spinal muscular atrophy (SMA), the most frequent genetic cause of early childhood lethality. In rare instances, however, individuals are asymptomatic despite carrying the same SMN1 mutations as their affected siblings, thereby suggesting the influence of modifier genes. We discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin 3 (PLS3) than their SMA-affected counterparts. We demonstrated that PLS3 is important for axonogenesis through increasing the F-actin level. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN down-regulation in motor neurons of SMA mouse embryos and in zebrafish. Our study suggests that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.

A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites

“…26,36 Another study reported families with unaffected SMN1-deleted females who had increased expression of the X chromosome gene plastin 3 (PLS3) compared with their SMA affected siblings. 9 Plastin 3 is important for axonogenesis and, therefore, was proposed as a protective modifier. It is possible that differential expression of PLS3 is modifying the SMA phenotype in the Hutterites, possibly accounting for the relatively early age of onset in the two affected boys and the milder phenotypes among females (including an asymptomatic woman), all of whom are homozygous for the same haplotype carrying 0 SMN1 and 2 SMN2 genes.…”

“…9,[25][26][27][28][29] The precise genetic modifiers that ameliorate the phenotype have not been determined in most cases, although a single base substitution in SMN2 (c.859G4C) enhances splicing of the gene, enabling it to partially or fully compensate for the lack of SMN1 in some cases. 25 However, the unaffected homozygous woman in our study did not carry this modifier.…”

“…The severity of SMA is modified by multiple factors, with the copy number of the homologous gene SMN2 being the major modifier. 3,[7][8][9] The SMN1 gene is located on chromosome 5q13, proximal to a nearly-identical homologous gene, SMN2. SMN2 copy number varies from zero to three copies per chromosome, whereas SMN1 copy number ranges from zero to 42 per chromosome.…”

Pathogenesis of proximal autosomal recessive spinal muscular atrophy

“…Moreover, since it has been shown that even diseased siblings with the same number of SMN2 genes can have different SMA phenotypes, many researchers thought that the SMN locus alone cannot explain the whole genetic basis for phenotypic variability of SMA [18,71]. To identify those putative SMA modifier genes, a transcriptome-wide differential expression analysis using total RNA from the lymphoblastoid cell lines derived from both unaffected and affected SMN1-deleted siblings was recently carried out by Wirth and collaborators [63]. In total, 18 transcripts showed a greater than threefold difference in expression, but only plastin 3 (PLS3, MIM# 300131) exhibited statistically significantly higher expression in fully asymptomatic siblings of all six SMA-discordant families analyzed [63].…”

“…To identify those putative SMA modifier genes, a transcriptome-wide differential expression analysis using total RNA from the lymphoblastoid cell lines derived from both unaffected and affected SMN1-deleted siblings was recently carried out by Wirth and collaborators [63]. In total, 18 transcripts showed a greater than threefold difference in expression, but only plastin 3 (PLS3, MIM# 300131) exhibited statistically significantly higher expression in fully asymptomatic siblings of all six SMA-discordant families analyzed [63]. All unaffected SMN1-deleted subjects were females and interestingly also the PST3 gene is localized on the sex-determining X chromosome.…”