West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
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.
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.|King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia.
Ali Abdullah
AA
Alfaiz
Division of Cell Biology, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany.
Verena
V
Müller
Department of Constitutional Cytogenetics, Lyon Hospices Civils, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.|CRNL, CNRS UMR 5292, INSERM U1028, Lyon, France.
Nadia
N
Boutry-Kryza
Center of Reference for Tuberous Sclerosis and Rare Epileptic Disorders, Hospices Civils de Lyon, Lyon, France.
Dorothée
D
Ville
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
Nicolas
N
Guex
Department of Pediatric Epileptology, Lyon Hospices Civils, Lyon, France.
Julitta
J
de Bellescize
Department of Pediatrics, Hopital Nord-Ouest, Villefranche-sur-Saône, France.
Clotilde
C
Rivier
Department of Constitutional Cytogenetics, Lyon Hospices Civils, Lyon, France.
Audrey
A
Labalme
Claude Bernard Lyon I University, Lyon, France.|Center of Reference for Tuberous Sclerosis and Rare Epileptic Disorders, Hospices Civils de Lyon, Lyon, France.
Vincent
V
des Portes
Department of Constitutional Cytogenetics, Lyon Hospices Civils, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.|CRNL, CNRS UMR 5292, INSERM U1028, Lyon, France.
Patrick
P
Edery
Department of Constitutional Cytogenetics, Lyon Hospices Civils, Lyon, France.
Marianne
M
Till
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
Ioannis
I
Xenarios
Department of Constitutional Cytogenetics, Lyon Hospices Civils, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.|CRNL, CNRS UMR 5292, INSERM U1028, Lyon, France.
Damien
D
Sanlaville
Division of Cell Biology, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany.
Johannes M
JM
Herrmann
Department of Constitutional Cytogenetics, Lyon Hospices Civils, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.|CRNL, CNRS UMR 5292, INSERM U1028, Lyon, France.
Gaétan
G
Lesca
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Alexandre
A
Reymond
D001665:Binding Sites; D017124:Conserved Sequence; D059472:Exome; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D005816:Genetic Complementation Test; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D020648:Peptide Elongation Factor 1; D020653:Peptide Elongation Factor G / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D013036:Spasms, Infantile / Q000235:genetics* / Q000473:pathology; D015003:Yeasts / Q000235:genetics
C000621464:GUF1 protein, human; D024101:Mitochondrial Proteins; D020648:Peptide Elongation Factor 1; D020653:Peptide Elongation Factor G; D020558:GTP Phosphohydrolases