Bi-allelic variants in DOHH, catalyzing the last step of hypusine biosynthesis, are associated with a neurodevelopmental disorder

Ziegler, Alban; Steindl, Katharina; Hanner, Ashleigh S.; Kar, Rajesh Kumar; Prouteau, Clément; Boland, Anne; Deleuze, Jean; Coubes, Christine; Bézieau, Stéphane; Küry, Sébastien; Maystadt, Isabelle; Mao, Morgane Le; Lenaers, Guy; Navet, Benjamin; Faivre, Laurence; Mau‐Them, Frédéric Tran; Zanoni, Paolo; Chung, Wendy K.; Rauch, Anita; Bonneau, Dominique; Park, Myung Hee

doi:10.1016/j.ajhg.2022.06.010

Cited by 20 publications

(29 citation statements)

References 30 publications

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“…The importance of the hypusination axis for neural development has been demonstrated in a recent study showing that neuronspecific ablation of eIF5A or DHS leads to impairments in neurodevelopment and cognitive functions in mice 38 . Individuals with certain variants of either eIF5A 37 or DOHH 39 display similar developmental delay and intellectual disability to those affected by DHS deficiency 22 . Hence, future research needs to investigate the effects of those mutations on the mechanisms of hypusination.…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders

et al. 2023

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Hypusination is a unique post-translational modification of the eukaryotic translation factor 5A (eIF5A) that is essential for overcoming ribosome stalling at polyproline sequence stretches. The initial step of hypusination, the formation of deoxyhypusine, is catalyzed by deoxyhypusine synthase (DHS), however, the molecular details of the DHS-mediated reaction remained elusive. Recently, patient-derived variants of DHS and eIF5A have been linked to rare neurodevelopmental disorders. Here, we present the cryo-EM structure of the human eIF5A-DHS complex at 2.8 Å resolution and a crystal structure of DHS trapped in the key reaction transition state. Furthermore, we show that disease-associated DHS variants influence the complex formation and hypusination efficiency. Hence, our work dissects the molecular details of the deoxyhypusine synthesis reaction and reveals how clinically-relevant mutations affect this crucial cellular process.

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Section: Discussionmentioning

confidence: 99%

Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders

et al. 2023

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“…DHPS generates the post-translational modification deoxyhypusine by conjugation of the aminobutyl moiety of spermidine on the lysine of eIF5A which is then matured to hypusine by DOHH ( Park et al, 1981 ). Over the years, elegant work has led to the structure of the nuclear shuttle for hypusinated eIF5A (Xpo4) ( Aksu et al, 2016 ), the description of RNA-binding properties for hypusinated eIF5A ( Xu et al, 2004 ), and reports on patients with mutations in eIF5A ( Faundes et al, 2021 ), DHPS ( Ganapathi et al, 2019 ), or DOHH ( Ziegler et al, 2022 ) that all showed neurodevelopmental phenotypes. Although until recently ( Lindner et al, 2021 ), the hypusine axis was never identified in the context of phagocytosis, several previous studies suggested its implication in vesicular trafficking, cytoskeleton organization, and immune cell regulation; all processes highly relevant for phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide CRISPR functional survey of the human phagocytosis molecular machinery

et al. 2023

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Phagocytosis, the process by which cells engulf large particles, plays a vital role in driving tissue clearance and host defense. Its dysregulation is connected to autoimmunity, toxic accumulation of proteins, and increased risks for infections. Despite its importance, we lack full understanding of all molecular components involved in the process. To create a functional map in human cells, we performed a genome-wide CRISPRko FACS screen that identified 716 genes. Mapping those hits to a comprehensive protein–protein interaction network annotated for functional cellular processes allowed retrieval of protein complexes identified multiple times and detection of missing phagocytosis regulators. In addition to known components, such as the Arp2/3 complex, the vacuolar-ATPase-Rag machinery, and the Wave-2 complex, we identified and validated new phagocytosis-relevant functions, including the oligosaccharyltransferase complex (MAGT1/SLC58A1, DDOST, STT3B, and RPN2) and the hypusine pathway (eIF5A, DHPS, and DOHH). Overall, our phagocytosis network comprises elements of cargo uptake, shuffling, and biotransformation through the cell, providing a resource for the identification of potential novel drivers for diseases of the endo-lysosomal system. Our approach of integrating protein–protein interaction offers a broadly applicable way to functionally interpret genome-wide screens.

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“…Gain-of-function mutations in the C-terminus of ODC have been connected to Bachmann-Bupp Syndrome (BABS; OMIM #619075) ( Bupp et al, 2018 ; Rajasekaran et al, 2021 ; VanSickle et al, 2021 ; Bupp et al, 2022 ) and loss-of-function mutations in spermine synthase are associated with Snyder-Robinson Syndrome (SRS) ( Albert et al, 1993 ; Cason et al, 2003 ; Starks et al, 2018 ). Patients with gene mutations in DHPS and bi-allelic variants in DOHH have recently been identified ( Ganapathi et al, 2019 ; Park et al, 2022 ; Ziegler et al, 2022 ). The DHPS-related disorder is referred to as DHPS deficiency or DHPS syndrome ( ) and is also known as neurodevelopmental disorder with seizures and speech and walking impairment (NEDSSWI; OMIM #618480).…”

Section: Discussionmentioning

confidence: 99%

“…Several mouse and zebrafish models to study eif5a1, eif5a2, Dhps, and Dohh are available and revealed that homozygous null-mutant mice were embryonic lethal, while heterozygous mice were viable and fertile ( Faundes et al, 2021 ; Kar et al, 2021 ; Mastracci et al, 2015 ; Nishimura et al, 2012 ; Pallmann et al, 2015 ; Sievert et al, 2014 ). Mutant mice with a temporal or region-specific knockout of eif5a1 or Dhps in the forebrain exhibit impairment in growth, lifespan, brain development, and cognitive functions ( Kar et al, 2021 ) and are similar to phenotypes described in humans ( Ziegler et al, 2022 ). These models will be useful for the development of future treatments against neurodevelopmental disorders caused by variants of these genes.…”

Section: Introductionmentioning

confidence: 99%

New K50R mutant mouse models reveal impaired hypusination of eif5a2 with alterations in cell metabolite landscape

et al. 2023

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The eukaryotic translation initiation factor 5A1 (eIF5A1) and 5A2 (eIF5A2) are important proteins in a variety of physiological and pathophysiological processes and their function has been linked to neurodevelopmental disorders, cancer, and virology. Here, we report two new genome-edited mouse models, generated using a CRISPR-Cas9 approach, in which the amino acid residue lysine 50 is replaced with arginine 50 (K50R) in eIF5A1 or in the closely related eIF5A2 protein. This mutation prevents the spermidine-dependent post-translational formation of hypusine, a unique lysine derivative that is necessary for activation of eIF5A1 and eIF5A2. Mouse brain lysates from homozygous eif5a2-K50R mutant mice (eif5a2K50R/K50R) confirmed the absence of hypusine formation of eIF5A2, and metabolomic analysis of primary mouse dermal fibroblasts revealed significant alterations in the metabolite landscape compared to controls including increased levels of tryptophan, kyrunenine, pyridoxine, NAD, riboflavin, FAD, pantothenate, and CoA. Further supported by new publicly available bioinformatics data, these new mouse models represent excellent in vivo models to study hypusine-dependent biological processes, hypusination-related disorders caused by eIF5A1 and eIF5A2 gene aberrations or mRNA expression dysregulation, as well as several major human cancer types and potential therapies.

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Bi-allelic variants in DOHH, catalyzing the last step of hypusine biosynthesis, are associated with a neurodevelopmental disorder

Cited by 20 publications

References 30 publications

Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders

Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders

A genome-wide CRISPR functional survey of the human phagocytosis molecular machinery

New K50R mutant mouse models reveal impaired hypusination of eif5a2 with alterations in cell metabolite landscape

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