Next up is Victor Faundes, who will talk about Impaired eIF5A function causes a craniofacial-neurodevelopmental syndrome that is partially rescued in model systems by spermidine #ASHG20
EIF5A was identified as a candidate developmental disorder gene through WES. Used the DDD resource to identify a further 6 individuals with EIF5A variants, defined a novel syndrome of developmental delay and other features #ASHG20
EIF5A resolves ribosomal stalling caused by polyproline tracts. Aimed to understand how this is disrupted by the variants seen in patients. Haploinsufficiency is the most likely mechanism #ASHG20
Explored the action of these variants in yeast - for two variants, impair growth. Frameshift variant results in a complete loss of viability. One other variant had no apparent phenotype #ASHG20
Variants reduce the interaction between EIF5A and the ribosome (80S), and results in increased free 60S. The reduced interaction can in part by explained by reduced total / hypusinated EIF5A #ASHG20
EIF5A variants reduce the synthesis of proteins with poly-proline tracts. Does this explain the clinical phenotype? Potentially - microcephaly genes are enriched for polyproline tracts #ASHG20
Can this phenotype be rescued with a drug? Spermidine is the substrate for hypusine, and can partially replace EIF5A. Partly improves growth and molecular defects in yeast. Zebrafish with KO eif5a have micrognathia, spermidine partially rescues this #ASHG20
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