2. Academic Validation
  3. West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1

West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1

  • Eur J Hum Genet. 2016 Jul;24(7):1001-8. doi: 10.1038/ejhg.2015.227.
Ali Abdullah Alfaiz 1 2 3,  Verena Müller 4,  Nadia Boutry-Kryza 5 6 7,  Dorothée Ville 8,  Nicolas Guex 1 2,  Julitta de Bellescize 9,  Clotilde Rivier 10,  Audrey Labalme 5,  Vincent des Portes 6 8,  Patrick Edery 5 6 7,  Marianne Till 5,  Ioannis Xenarios 1 2,  Damien Sanlaville 5 6 7,  Johannes M Herrmann 4,  Gaétan Lesca 5 6 7,  Alexandre Reymond 1
Affiliations

Affiliations

  • 1 Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
  • 2 Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
  • 3 King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia.
  • 4 Division of Cell Biology, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany.
  • 5 Department of Constitutional Cytogenetics, Lyon Hospices Civils, Lyon, France.
  • 6 Claude Bernard Lyon I University, Lyon, France.
  • 7 CRNL, CNRS UMR 5292, INSERM U1028, Lyon, France.
  • 8 Center of Reference for Tuberous Sclerosis and Rare Epileptic Disorders, Hospices Civils de Lyon, Lyon, France.
  • 9 Department of Pediatric Epileptology, Lyon Hospices Civils, Lyon, France.
  • 10 Department of Pediatrics, Hopital Nord-Ouest, Villefranche-sur-Saône, France.
PMID: 26486472 DOI: 10.1038/ejhg.2015.227
Abstract

West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births. To get better insights on the genetic of this pathology, we exome-sequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings. GUF1 encodes a protein essential in conditions that counteract faithful protein synthesis: it is able to remobilize stuck ribosomes and transiently inhibit the elongation process to optimize protein synthesis. The variant identified in the WS family changes an alanine residue conserved in all eukaryotic organisms and positioned within the tRNA-binding moiety of this nuclear genome-encoded mitochondrial translational elongation factor. Yeast complementation assays show that the activity of GUF1(A609S) is modified in suboptimal environments. We suggest a new link between improper assembly of respiratory chain complexes and WS.

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