Pre-natal manifestation of systemic developmental abnormalities in spinal muscular atrophy

Anna Abigail Lydia Motyl, Kiterie Faller, Ewout J. N. Groen, Rachel Kline, Samantha Eaton, Leire Ledahawsky, Helena Chaytow, Douglas J Lamont, Thomas Wishart, Yu-ting Huang, Tom Gillingwater

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in survival motor neuron 1 (SMN1). SMN-restoring therapies have recently emerged; however, pre clinical and clinical studies revealed a limited therapeutic time-window and systemic aspects of the disease. This raises a fundamental question of whether SMA has pre-symptomatic, developmental components to disease pathogenesis. We have addressed this by combining micro-computed tomography (µCT) and comparative proteomics to examine systemic pre30 symptomatic changes in a prenatal mouse model of SMA. Quantitative µCT analyses revealed that SMA embryos were significantly smaller than littermate controls, indicative of general developmental delay. More specifically, cardiac ventricles were smaller in SMA hearts, whilst liver and brain remained unaffected. In order to explore the molecular consequences of SMN depletion during development, we generated comprehensive, high-resolution, proteomic profiles of neuronal and non-neuronal organs in SMA mouse embryos. Significant molecular perturbations were observed in all organs examined, highlighting tissue-specific prenatal molecular phenotypes in SMA. Together, our data demonstrate considerable systemic changes at an early, pre-symptomatic stage in SMA mice, revealing a significant developmental component to SMA pathogenesis.
Original languageEnglish
Pages (from-to)2674 - 2683
JournalHuman Molecular Genetics
Issue number16
Early online date9 Jul 2020
Publication statusE-pub ahead of print - 9 Jul 2020

Keywords / Materials (for Non-textual outputs)

  • neuromuscular diseases
  • phenotype
  • congenital abnormality
  • mutation
  • embryo
  • heart ventricle
  • motor neurons
  • spinal muscular atrophy
  • brain
  • heart
  • liver
  • mice
  • proteomics
  • developmental delay
  • x-ray
  • microtomography
  • perturbations


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