ReferenceID 2881
Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine
Nat Commun
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 contai
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Record Fields
Scalar fields from the final reference record.
- Reference Id
- 2881
- Evidence Id
- 19471
- Core Evidence Id
- 19471
- Source Reference Id
- 5747
- Herb2 Reference Id
- HBREF006544
- Subject Paper Key
- HBIN044493_33547280
- Pubmed Id
- 33547280
- Doi
- 10.1038/s41467-021-21053-2
- Paper Title
- Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine
- Paper 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 microM 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.
- Journal
- Nat Commun
- Publish Year
- 2021
- Experiment Subject
- human; yeast; zebrafish
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Eif5a-related Disorder; Microcephaly; Dysmorphism; Micrognathia; Developmental Delay
- Paper Title Cn
- Paper Title En
- Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine
- Bilingual Status
- semi_complete