Spinal Muscular Atrophy (SMA) is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Decreased levels of, cell-ubiquitous, SMN protein is associated with a range of systemic pathologies reported in severe patients. Despite high levels of SMN protein in normal liver, there is no comprehensive study of liver pathology in SMA. We describe failed liver development in response to reduced SMN levels, in a mouse model of severe SMA. The SMA liver is dark red, small and has: iron deposition; immature sinusoids congested with blood; persistent erythropoietic elements and increased immature red blood cells; increased and persistent megakaryocytes which release high levels of platelets found as clot-like accumulations in the heart. Myelopoiesis in contrast, was unaffected. Further analysis revealed significant molecular changes in SMA liver, consistent with the morphological findings. Antisense treatment from birth with PMO25, increased lifespan and ameliorated all morphological defects in liver by postnatal day 21. Defects in the liver are evident at birth, prior to motor system pathology, and impair essential liver function in SMA. Liver is a key recipient of SMA therapies, and systemically delivered antisense treatment, completely rescued liver pathology. Liver therefore, represents an important therapeutic target in SMA.
Bibliographical noteWe would like to thank Lucas Fraga who helped with primer design and Alison Thomson for tissue collection. We would also like to acknowledge the Microscopy and Histology Core Facility at the University of Aberdeen for the use of their facilities. SHP is funded by Anatomical Society, Euan MacDonald Centre for Motor Neurone Disease Research and an Elphinstone Scholarship for ES from the University of Aberdeen. THG is funded by SMA Trust (UK SMA Research Consortium award), Muscular Dystrophy UK, and Anatomical Society (PhD Studentship). FM is funded by Medical Research Council, SMA-Europe and the National Institute for Health Research Biomedical Research Centre and Great Ormond Street Hospital Children’s Charity. HZ is funded by SMA-Europe and the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.
Corrigendum: Survival Motor Neuron (SMN) protein is required for normal mouse liver development Published online: 10 November 2016
- experimental models of disease
- neuromuscular disease