bims-hypusi 2025-12-21 papers

Am J Med Genet A. 2025 Dec 18.

Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.

Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.

Keywords: Bachmann–Bupp syndrome; DHPS; DOHH; EIF5A; Faundes‐Banka syndrome; ODC1; SMS; Snyder–Robinson syndrome; deoxyhypusine hydroxylase disorder; deoxyhypusine synthase deficiency

DOI: https://doi.org/10.1002/ajmga.70029

Biochem J. 2025 Dec 17. 482(24): 1973-1992

Opposite effects of spermidine and GC7 in cell culture are dictated by distinct molecular targets.

Tomoaki Tahara, Rosa Bordone, Antonio Francesco Campese, Noemi Martina Cantale Aeo, Roberta Astolfi, Sonia Coni, Rino Ragno, Gianluca Canettieri, Enzo Agostinelli.

Spermidine (SPD) and related polyamines are small polycationic molecules typically elevated in cancer cells, where their depletion suppresses tumor growth both in vitro and in vivo. Paradoxically, SPD has also been proposed as a dietary supplement for its potential health benefits, including cancer prevention, prompting considerable interest in elucidating its mechanisms of action. In vitro studies using cultured cancer cell lines treated with exogenous SPD have yielded conflicting results, with reports of enhanced proliferation, cytotoxicity, or modulation of autophagy. To address these discrepancies, we used polyamine-depleted colorectal cancer (CRC) cells to systematically evaluate SPD's effects across a range of concentrations. Following depletion with difluoromethylornithine, SPD exhibited a biphasic response: at low concentrations (<20 µM), it promoted proliferation via deoxyhypusine synthase (DHPS)-dependent hypusination of eukaryotic initiation factor 5A, whereas high concentrations (>100 µM) induced DHPS-independent cytotoxicity mediated by bovine serum amine oxidase (BSAO) activity in fetal bovine serum. High SPD doses transiently inhibited the autophagic flux, while low doses did not display any effect at all time points tested. The DHPS inhibitor GC7 (N1-guanyl-1,7-diaminoheptane) suppressed SPD-induced proliferation at low concentrations and unexpectedly prevented cytotoxicity at high concentrations. Kinetic assays revealed that GC7 also inhibits BSAO in a non-competitive manner (Ki ≈ 300 nM), independent of DHPS. In silico docking analysis indicated that GC7 binds BSAO via non-covalent interactions, outside the topaquinone organic cofactor site. These findings clarify the concentration-dependent effects of SPD in CRC cells, reconcile conflicting in vitro data, and identify BSAO as a previously unrecognized target of GC7, providing new mechanistic insights into polyamine-driven cancer biology.

Keywords: N1-guanyl-1,7-diaminoheptane, GC7; bovine serum amine oxidase, BSAO; deoxyhypusine synthase, DHPS; eIF5A; molecular docking; spermidine, SPD

DOI: https://doi.org/10.1042/BCJ20253298

Nat Commun. 2025 Dec 13.

Inhibiting translation elongation by reducing eIF5A activity induces feedback inhibition of initiation, limiting tumour cell proliferation.

Cancer development is associated with dysregulation of the translatome, and targeting canonical eukaryotic initiation and elongation factors can offer treatment avenues for various neoplasms. Emerging evidence indicates that dysregulated mRNA elongation, involving alterations in eEF2 activity and eIF5A expression, also contributes to tumour cell growth. In this study, we investigate whether targeting eIF5A with the inhibitor GC7 is a viable strategy to curtail aberrant cell growth. Our findings demonstrate that inhibiting elongation by reducing eIF5A activity induces feedback inhibition of initiation through eIF2α phosphorylation, decreasing ternary complex formation and shutting down bulk protein synthesis. Employing dynamic SILAC, we identify proteins impacted by reduced eIF5A activity, and show their decreased translation results from feedback inhibition to initiation or other processes downstream of eIF5A. Decreased eIF5A activity impairs mitochondrial function, which activates signalling through HRI to eIF2α phosphorylation, reducing cancer cell proliferation. These effects are reversed by treatment with the integrated stress response inhibitor, implying that the impact of GC7 on cancer cell proliferation is mediated via translation initiation rather than elongation inhibition. These data suggest that eIF5A inhibition could be used to target cancer cells that depend on mitochondrial function for their proliferation and survival.

DOI: https://doi.org/10.1038/s41467-025-66531-z