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

Research output: Contribution to journalArticle

Original languageEnglish
JournalHuman Molecular Genetics
Early online date9 Jul 2020
Publication statusE-pub ahead of print - 9 Jul 2020


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.

    Research areas

  • 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

ID: 155079859