2. Academic Validation
  3. Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine

Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine

  • Nat Commun. 2021 Feb 5;12(1):833. doi: 10.1038/s41467-021-21053-2.
Víctor Faundes 1 2,  Martin D Jennings 3 4,  Siobhan Crilly 5,  Sarah Legraie 1,  Sarah E Withers 5,  Sara Cuvertino 1,  Sally J Davies 6,  Andrew G L Douglas 7 8,  Andrew E Fry 6 9,  Victoria Harrison 7,  Jeanne Amiel 10 11 12,  Daphné Lehalle 10,  William G Newman 1 13,  Patricia Newkirk 14,  Judith Ranells 14,  Miranda Splitt 15,  Laura A Cross 16 17,  Carol J Saunders 18 19 20,  Bonnie R Sullivan 16 17,  Jorge L Granadillo 21,  Christopher T Gordon 11 12,  Paul R Kasher 22 23,  Graham D Pavitt 24 25,  Siddharth Banka 26 27
Affiliations

Affiliations

  • 1 Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • 2 Laboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile.
  • 3 Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • 4 Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
  • 5 Division of Neuroscience & Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • 6 Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
  • 7 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
  • 8 Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
  • 9 Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
  • 10 Department of Genetics, AP-HP, Hôpital Necker Enfants Malades, Paris, France.
  • 11 1Laboratory of Embryology and Genetics of Human Malformations, INSERM UMR 1163, Institut Imagine, Paris, France.
  • 12 Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
  • 13 Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
  • 14 Division of Genetics and Metabolism, Department of Pediatrics, University of South Florida, Tampa, FL, UK.
  • 15 Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne, UK.
  • 16 Division of Clinical Genetics, Children's Mercy, Kansas City, MO, USA.
  • 17 Department of Pediatrics, University of Missour-Kansas City, Kansas City, MO, USA.
  • 18 Center for Pediatric Genomic Medicine Children's Mercy, Kansas City, MO, USA.
  • 19 School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.
  • 20 Department of Pathology and Laboratory Medicine, Children's Mercy, Kansas City, MO, USA.
  • 21 Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
  • 22 Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. [email protected].
  • 23 Division of Neuroscience & Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. [email protected].
  • 24 Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. [email protected].
  • 25 Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. [email protected].
  • 26 Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. [email protected].
  • 27 Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK. [email protected].
PMID: 33547280 DOI: 10.1038/s41467-021-21053-2
Abstract

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.

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