Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular
disorder resulting from biallelic alterations of the SMN1 gene:
deletion, gene conversion or, in rare cases, intragenic variants. The
disease severity is mainly influenced by the copy number of SMN2,
a nearly identical gene, which produces only low amounts of full-length
(FL) mRNA. Here we describe the first example of retrotransposon
insertion as a pathogenic SMN1 mutational event. The 50-year-old
patient is clinically affected by SMA type III with a diagnostic odyssey
spanning nearly 30 years. Despite a mild disease course, he carries a
single SMN2 copy. Using Exome Sequencing and Sanger sequencing,
we characterized a SVA-F retrotransposon inserted in SMN1 intron
7. Using RT-PCR and RNASeq experiments on lymphoblastoid cell lines, we
documented the dramatic decrease of FL transcript production in the
patient compared to subjects with the same SMN1 and SMN2
copy number, thus validating the pathogenicity of this SVA insertion. We
characterized the mutant FL-SMN1-SVA transcript and showed that it is
subject to degradation by nonsense-mediated mRNA decay. The stability of
the SMN-SVA protein may explain the mild course of the disease. This
observation exemplifies the role of retrotransposons in human genetic
disorders.