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Retrotransposon insertion as a novel mutational cause of spinal muscular atrophy
  • +9
  • Pascale Saugier-Veber,
  • Myriam Vezain,
  • Christel Thauvin-Robinet,
  • Yoann VIAL,
  • Sophie Coutant,
  • severine drunat,
  • Jon Andoni Urtizberea,
  • Anne Rolland,
  • Agnès Jacquin-Piques,
  • Séverine Fehrenbach,
  • Gaël Nicolas,
  • François Lecoquierre
Pascale Saugier-Veber
Centre Hospitalier Universitaire de Rouen

Corresponding Author:[email protected]

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Myriam Vezain
Centre Hospitalier Universitaire de Rouen
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Christel Thauvin-Robinet
Centre Hospitalier Universitaire Dijon Bourgogne
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Yoann VIAL
Centre Hospitalier Universitaire de Rouen
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Sophie Coutant
Centre Hospitalier Universitaire de Rouen
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severine drunat
Hopital Universitaire Robert-Debre Departement de genetique
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Jon Andoni Urtizberea
Hopital Universitaire Pitie Salpetriere
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Anne Rolland
Centre Hospitalier Universitaire de Rouen
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Agnès Jacquin-Piques
Centre Hospitalier Universitaire Dijon Bourgogne
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Séverine Fehrenbach
Centre Hospitalier Universitaire de Rouen
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Gaël Nicolas
Centre Hospitalier Universitaire de Rouen
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François Lecoquierre
Centre Hospitalier Universitaire de Rouen
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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.