A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype.
Proximal spinal muscular atrophy (SMA) is a neurodegenerative disease caused by low levels of the survival motor neuron (SMN) protein. In humans, SMN1 and SMN2 encode the SMN protein. In SMA patients, the SMN1 gene is lost and the remaining SMN2 gene only partially compensates. Mediated by a C>T nucleotide transition in SMN2, the inefficient recognition of exon 7 by the splicing machinery results in low levels of SMN. Because the SMN2 gene is capable of expressing SMN protein, correction of SMN2 splicing is an attractive therapeutic option. Although current mouse models of SMA characterized by Smn knock-out alleles in combination with SMN2 transgenes adequately model the disease phenotype, their complex genetics and short lifespan have hindered the development and testing of therapies aimed at SMN2 splicing correction. Here we show that the mouse and human minigenes are regulated similarly by conserved elements within in exon 7 and its downstream intron. Importantly, the C>T mutation is sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C>T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibit exon 7 skipping and mild adult onset SMA characterized by muscle weakness, decreased activity and an alteration of the muscle fibers size. This Smn C>T mouse represents a new model for an adult onset form of SMA (type III/IV) also know as the Kugelberg-Welander disease.
Gladman
Jordan T
JT
Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
Bebee
Thomas W
TW
Edwards
Chris
C
Wang
Xueyong
X
Sahenk
Zarife
Z
Rich
Mark M
MM
Chandler
Dawn S
DS
D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D005091:Exons; D006801:Humans; D007438:Introns; D051379:Mice; D008822:Mice, Transgenic; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D010641:Phenotype; D012326:RNA Splicing; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein