title: Survival Motor Neuron (SMN) protein is required for normal mouse liver development.
abstract: 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.
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.|Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Eva
authors.initials: E
authors.lastname: Szunyogova
authors.affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Gillian K
authors.initials: GK
authors.lastname: Maxwell
authors.affiliation: Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom.|Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Powis
authors.affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom.|Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.|Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Simon H
authors.initials: SH
authors.lastname: Parson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000254:growth & development* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein