Retrotransposon insertion as a novel mutational cause of spinal muscular atrophy

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 in uenced by the copy number of SMN2, a nearly identical gene, which produces only low amounts of full-length (FL) mRNA. Here we describe the rst 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 exempli es the role of retrotransposons in human genetic disorders.

Analysis of spinal muscular atrophy carrier screening results in 32,416 pregnant women and 7,231 prepregnant women

“…Approximately 95% of SMA patients are caused by loss of function in the SMN1 due to E7 lost or both E7 and E8 lost, while the remaining individuals may exhibit a genetic variation where one copy of the gene is lost and the other copy contains a mutation within the gene ( 7 ). The disease severity is mainly influenced by the copy number of survival motor neuron 2 ( SMN2 ), a nearly identical gene and highly similar to SMN1 , which produces only less functional protein ( 8 ). The SMN1 and SMN2 are very similar in terms of their DNA sequences, with only five nucleotides differentiating them.…”

A Genome-Wide Screen for the Exonisation of Reference SINE-VNTR-Alus and Their Expression in CNS Tissues of Individuals with Amyotrophic Lateral Sclerosis

“…To date, at least 26 SVAs have been identified as the genetic cause of diseases such as cancer predisposition syndromes, X-linked dystonia parkinsonism, antithrombin deficiency, and spinal muscular atrophy [12][13][14]. More than half of these insertions caused aberrant splicing patterns through mechanisms such as exon skipping, exonisation events (which introduced premature stop codons), or the activation of cryptic splice sites.…”