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

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.

Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice

“…Recent genetic studies have provided evidence that certain variants in the EIF5A (27) J o u r n a l P r e -p r o o f or DHPS gene (28) are associated with rare neurodevelopmental disorders in humans. Furthermore, individuals with DOHH variants who display similar developmental delay and intellectual disability have also been identified (Ziegler A. et al, Unpublished results), underscoring the importance of each step of the hypusine modification pathway and thereby the critical role of the hypusinated eIF5A in neurodevelopment in humans (29).…”

“…From whole genome exome sequencing and genetic analysis, biallelic DHPS variants were identified as the cause of a rare autosomal recessive neurodevelopmental disorder (28). More recently, germ line, de novo, heterozygous EIF5A variants were also reported to be associated with a neurodevelopmental disorder (27) Emx1-Cre mediated knockout of Eif5a or Dhps was achieved by two-step breeding. First, Eif5a fl/fl (8) or Dhps fl/fl (7) mouse was mated with Emx1-IRES-Cre mouse (30) to generate either Eif5a fl/+ ;Emx1-Cre or Dhps fl/+ ;Emx1-Cre mouse, which was mated again with mice carrying their respective homozygous floxed allele to produce either Eif5a fl/fl ; Emx1-Cre or Dhps fl/fl ;Emx1-Cre mice.…”

Overlapping regions of Caf20 mediate its interactions with the mRNA-5′cap-binding protein eIF4E and with ribosomes

“…However, there is no evidence that we are aware of, that Caf20 functions directly or indirectly to impact colliding ribosomes. eIF5A is a factor that is recruited to stalled, collided elongating ribosomes 31 and mutants affecting eIF5A recruitment to ribosomes were shown to cause an increase in polysome:monosome ratios 32 . In contrast here Caf20 mutants caused reduced polysome:monosome ratios (Fig.…”

Hypusination, a Metabolic Posttranslational Modification of eIF5A in Plants during Development and Environmental Stress Responses

“…Several defects in hypusination could be restored by exogenous Spd, as studied in mice by Schroeder et al ( 2021) [52]. The newest results indicate that impaired eIF5A hypusination can cause serious Mendelian disorder in humans, which could be partly restored by Spd supplementation [53]. It is important to note that during Spd supplementation, neither the eIF5A expression nor hypusination increased, suggesting a potential mechanism and additional role of this PA. Spd has more functions that are needed for optimal cell growth and development.…”