Of SMN in mice and men: a therapeutic opportunity

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease that predominantly affects motor neurons, resulting in progressive muscular atrophy and weakness. SMA arises due to insufficient survival motor neuron (SMN) protein levels as a result of homozygous disruption of the SMN1 gene. SMN upregulation is a promising and potent treatment strategy for this currently incurable condition. In this issue of the JCI, two independent research groups report novel observations in mouse models of severe SMA that provide hope that this approach will afford meaningful benefit to individuals with SMA.

Figure 1. SMA is a neurodegenerative disease that predominantly affects motor neurons.

SMA is caused by insufficient levels of SMN protein as a result of homozygous disruption of the SMN1 gene. The primary target of SMN deficiency appears to be a relatively selective degeneration of motor neurons in the anterior horn cells of the brainstem and spinal cord, resulting in skeletal muscle atrophy.

Figure 2. Gene organization and expression in the region of human chromosome 5q containing the SMN1 and SMN2 genes.

SMN is one of four duplicated genes within a duplicated inverted 500-bp region on chromosome 5q. The two copies of SMN differ by a few base pairs with only two of them being in the exonic sequence. Functionally critical is the single nucleotide difference in exon 7 at position 840. Although translationally silent, the C→T transition in SMN2 affects splicing. SMN is one of four genes in this inverted duplicated region; the others have not been clearly demonstrated to contribute to the pathogenesis of SMA. H4F5, protein 4F5; NAIP, NLR family, apoptosis inhibitory protein.