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

Anna A L Motyl,Leire M Ledahawsky,Thomas H Gillingwater,Yu-Ting Huang,Samantha L Eaton,Thomas M Wishart,Ewout J N Groen,Helena Chaytow,Kiterie M E Faller,Rachel A Kline,Douglas J Lamont

doi:10.1093/hmg/ddaa146

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in survival motor neuron 1 (SMN1). SMN-restoring therapies have recently emerged; however, preclinical and clinical studies revealed a limited therapeutic time window and systemic aspects of the disease. This raises a fundamental question of whether SMA has presymptomatic, developmental components to disease pathogenesis. We have addressed this by combining micro-computed tomography (μCT) and comparative proteomics to examine systemic pre-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, presymptomatic stage in SMA mice, revealing a significant developmental component to SMA pathogenesis.

Highlights

Spinal Muscular Atrophy (SMA) is the second most common autosomal recessive disorder in46 humans, after cystic fibrosis: with 2% of people carrying an Spinal muscular atrophy (SMA)-associated mutation, this 47 disease affects 1 in 6,000-10,000 live births and is the leading genetic cause of infant death [1,2]
Most studies on pre-symptomatic SMA in the Taiwanese mouse model have focused on 86 postnatal phenotypes
Development, we examined a range of organs, including the brain, spinal cord, liver, heart, and skeletal muscle

Summary

Introduction

humans, after cystic fibrosis: with 2% of people carrying an SMA-associated mutation, this disease affects 1 in 6,000-10,000 live births and is the leading genetic cause of infant death [1,2]. SMA is primarily a neurodegenerative disease characterised by loss of lower motor. neurons and muscle atrophy [3,4,5]. in the survival motor neuron 1 gene (SMN1) [6], leading to insufficient production of full-. Mouse embryos in which Smn has been 53 genetically knocked out die around the peri-implantation stage [9]. In late 2016, Spinraza (nusinersen) became the first FDA-approved drug to treat SMA (5, 56 10,11,12,13,14).

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Conclusion