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Review
. 2024 Jun 3:87:102210.
doi: 10.1016/j.gde.2024.102210. Online ahead of print.

Exploring pseudouridylation: dysregulation in disease and therapeutic potential

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Free article
Review

Exploring pseudouridylation: dysregulation in disease and therapeutic potential

Maria Guillen-Angel et al. Curr Opin Genet Dev. .
Free article

Abstract

Pseudouridine (Ψ), the most abundant RNA modification, plays a role in pre-mRNA splicing, RNA stability, protein translation efficiency, and cellular responses to environmental stress. Dysregulation of pseudouridylation is linked to human diseases. This review explores recent insights into the role of RNA pseudouridylation alterations in human disorders and the therapeutic potential of Ψ. We discuss the impact of the reduction of Ψ levels in ribosomal, messenger, and transfer RNA in RNA processing, protein translation, and consequently its role in neurodevelopmental diseases and cancer. Furthermore, we review the success of N1-methyl-Ψ messenger RNA vaccines against COVID-19 and the development of RNA-guided pseudouridylation enzymes for treating genetic diseases caused by premature stop codons.

Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Review
. 2024 May 29:S1043-2760(24)00124-3.
doi: 10.1016/j.tem.2024.05.006. Online ahead of print.

Increased hepatic gluconeogenesis and type 2 diabetes mellitus

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Review

Increased hepatic gluconeogenesis and type 2 diabetes mellitus

Emma Barroso et al. Trends Endocrinol Metab. .

Abstract

Abnormally increased hepatic gluconeogenesis is a significant contributor to hyperglycemia in the fasting state in patients with type 2 diabetes mellitus (T2DM) due to insulin resistance. Metformin, the most prescribed drug for the treatment of T2DM, is believed to exert its effect mainly by reducing hepatic gluconeogenesis. Here, we discuss how increased hepatic gluconeogenesis contributes to T2DM and we review newly revealed mechanisms underlying the attenuation of gluconeogenesis by metformin. In addition, we analyze the recent findings on new determinants involved in the regulation of gluconeogenesis, which might ultimately lead to the identification of novel and targeted treatment strategies for T2DM.

Keywords: AMPK; glucagon; insulin; lactate; metformin.

Conflict of interest statement

Declaration of interests No interests are declared.

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. 2024 May 30;16(1):72.
doi: 10.1186/s13073-024-01339-y.

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

Affiliations

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

Sissy Bassani et al. Genome Med. .

Abstract

Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.

Methods: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.

Results: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation.

Conclusions: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

Keywords: Horseshoe kidney; Intellectual disability; Mesomelic dysplasia; Transcriptome; Zebrafish model.

Conflict of interest statement

Annabelle Tuttle, Houda Zghal Elloumi and Chaofan Zhang are employees of GeneDx and Desiree DeMille works for ARUP Laboratories. James R. Lupski has stock ownership in 23andMe and is a paid consultant for Genome International. Claudia M.B. Carvalho provides consulting service for Ionis Pharmaceuticals. The other authors have no competing interests to declare.

Update of

  • Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.
    Bassani S, Chrast J, Ambrosini G, Voisin N, Schütz F, Brusco A, Sirchia F, Turban L, Schubert S, Jamra RA, Schlump JU, DeMille D, Bayrak-Toydemir P, Nelson GR, Wong KN, Duncan L, Mosera M, Gilissen C, Vissers LELM, Pfundt R, Kersseboom R, Yttervik H, Hansen GÅM, Falkenberg Smeland M, Butler KM, Lyons MJ, Carvalho CMB, Zhang C, Lupski JR, Potocki L, Flores-Gallegos L, Morales-Toquero R, Petit F, Yalcin B, Tuttle A, Elloumi HZ, Mccormick L, Kukolich M, Klaas O, Horvath J, Scala M, Iacomino M, Operto F, Zara F, Writzl K, Maver A, Haanpää MK, Pohjola P, Arikka H, Iseli C, Guex N, Reymond A. Bassani S, et al. medRxiv [Preprint]. 2024 Jan 17:2024.01.14.24301100. doi: 10.1101/2024.01.14.24301100. medRxiv. 2024. Update in: Genome Med. 2024 May 30;16(1):72. doi: 10.1186/s13073-024-01339-y. PMID: 38293053 Free PMC article. Updated. Preprint.

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