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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&gt;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&gt;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&gt;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&gt;T mouse represents a new model for an adult onset form of SMA (type III/IV) also know as the Kugelberg–Welander disease.

A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype