A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease. Loss of the survival motor neuron (SMN1) gene, in the presence of the SMN2 gene causes SMA. SMN functions in snRNP assembly in all cell types, however, it is unclear how this function results in specifically motor neuron cell death. Lack of endogenous mouse SMN (Smn) in mice results in embryonic lethality. Introduction of two copies of human SMN2 results in a mouse with severe SMA, while one copy of SMN2 is insufficient to overcome embryonic lethality. We show that SMN(A111G), an allele capable of snRNP assembly, can rescue mice that lack Smn and contain either one or two copies of SMN2 (SMA mice). The correction of SMA in these animals was directly correlated with snRNP assembly activity in spinal cord, as was correction of snRNA levels. These data support snRNP assembly as being the critical function affected in SMA and suggests that the levels of snRNPs are critical to motor neurons. Furthermore, SMN(A111G) cannot rescue Smn-/- mice without SMN2 suggesting that both SMN(A111G) and SMN from SMN2 undergo intragenic complementation in vivo to function in heteromeric complexes that have greater function than either allele alone. The oligomer composed of limiting full-length SMN and SMN(A111G) has substantial snRNP assembly activity. Also, the SMN(A2G) and SMN(A111G) alleles in vivo did not complement each other leading to the possibility that these mutations could affect the same function.

SMN - A chaperone for nuclear RNP social occasions?

“…25,106,107 Furthermore, mutations that completely disrupt SMN's ability to self-oligomerize display severe phenotypes in human SMA patients as well as in animal models. 86,[108][109][110][111][112][113] Despite this strong correlation, the composition and stoichiometry of the various complexes formed by SMN are not well understood. In vitro, SMN-Gem2 exists as a stable heterodimer that, for purposes of discussing higher order oligomerization, can be considered as a single structural unit.…”

Developmental arrest of Drosophila survival motor neuron (Smn) mutants accounts for differences in expression of minor intron-containing genes

“…Although SMN may well have snRNP-independent functions (Carrel et al 2006;Burghes and Beattie 2009), the role of SMN in snRNP assembly and splicing continues to be a central focus of much of the research into SMA etiology (Winkler et al 2005;Gabanella et al 2007;Zhang et al 2008;Bäumer et al 2009;Workman et al 2009). Nevertheless, it remains unclear how disruption of a ubiquitously required process leads to a neuromuscular phenotype.…”

Modeling Spinal Muscular Atrophy in Mouse: A Disease of Splicing, Stability, and Timing

“…While U snRNP maturation is the primary function of SMN, other functions of SMN in the axon or at the NMJ may still contribute to SMA pathology www.intechopen.com for intragenic complementation between the SMN from SMN2 and the mutant A111G SMN protein. Analysis of snRNP assembly in the severe Line89 mice also showed reduced U4 and minor spliceosomal snRNP maturation that was subsequently rescued by the expression of the A111G transgene (Workman et al 2009). …”