Diverse species-specific phenotypic consequences of loss of function Sorting Nexin 14 mutations

Dale Bryant, Marian Seda, Emma Peskett, Constance Maurer, Gideon Pomeranz, Marcus Ghosh, Thomas Hawkins, James Cleak, Sanchari Datta, Hanaa Hariri, Kaitlyn M. Eckert, Daniyal J. Jafree, Claire Walsh, Charalambos Demetriou, Miho Ishida, Cristina Alemán-Charlet, Letizia Vestito, Rimante Seselgyte, Jeffrey G. McDonald, Maria Bitner-GlindziczMyriam Hemberger, Jason Rihel, Lydia Teboul, Mike Henne, Dagan Jenkins, Gudrun E. Moore, Philip Stanier

Research output: Contribution to journalArticlepeer-review


Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. SCAR20 is understood to involve subcellular disruption to autophagy and lipid metabolism. Previously reported studies on the phenotypic consequences of SNX14 mutations have been limited to in vitro investigation of patient-derived dermal fibroblasts, laboratory engineered cell lines and developmental analysis of zebrafish morphants. In addition, studies have investigated the biochemical roles of SNX14 homologues Snz (Drosophila) and Mdm1 (yeast) which have demonstrated an important role during lipid biogenesis. This study investigates the impact of constitutive Snx14 mutations in laboratory species: mice and zebrafish. Loss of SNX14 in mice was found to be embryonic lethal around mid-gestation. This is due to placental pathology that involves severe disruption to syncytiotrophoblast cell differentiation. Zebrafish carrying a homozygous, maternal zygotic snx14 genetic loss-of-function mutation contrasts with other vertebrates, being both viable and anatomically normal. Whilst no obvious behavioural effects were observed, elevated levels of neutral lipids and phospholipids resemble previously reported effects on lipid homeostasis in other species. The biochemical role of SNX14 therefore appears largely conserved through evolution while the overall consequences of loss of function varies considerably between species. New mouse and zebrafish models therefore provide valuable insights into the functional importance of SNX14 with distinct opportunities for investigating its cellular and metabolic function in vivo.

Original languageEnglish (US)
JournalUnknown Journal
StatePublished - Nov 11 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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