Poison exons: tuning RNA splicing for targeted gene regulation

Trends in Pharmacological Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

---

Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay

PLoS Genetics, Journal Year: 2024, Volume and Issue: 20(5), P. e1011279 - e1011279

Published: May 15, 2024

The leiomodin (Lmod) family of actin-binding proteins play a critical role in muscle function, highlighted by the fact that mutations all three members (LMOD1-3) result human myopathies. Mutations cardiac predominant isoform, LMOD2 lead to severe neonatal dilated cardiomyopathy. Most disease-causing LMOD gene are nonsense, or frameshift, predicted expression truncated proteins. However, nearly cases disease, little no protein is expressed. We show here nonsense-mediated mRNA decay, cellular mechanism which eliminates mRNAs with premature termination codons, underlies loss mutant from two independent mutations. Furthermore, we generated steric-blocking oligonucleotides obstruct deposition exon junction complex, preventing decay transcripts, thereby restoring expression. Our investigation lays initial groundwork for potential therapeutic intervention LMOD-linked

Language: Английский

---

Germline genetic variants in young-onset sporadic pituitary macroadenomas: A multigene panel analysis

Journal of Clinical & Translational Endocrinology, Journal Year: 2025, Volume and Issue: unknown, P. 100389 - 100389

Published: April 1, 2025

Mutations in several genes have been associated with familial forms of pituitary adenomas. Sporadic adenomas (i.e. no family history or coexistent endocrine tumours) are also occasionally found to result from germline mutations these genes, especially young patients larger tumours. The aim this study was determine the frequency young-onset sporadic macroadenomas. A cohort 225 Portuguese macroadenomas diagnosed before age 40 years studied by whole exome sequencing (WES) followed analysis a virtual panel 29 that predisposition Pathogenic and likely pathogenic variants were identified 16 (7.1 %) patients. affected AIP (n = 4), PMS2 MEN1 2), VHL CDH23 1), MSH2 SDHB TP53 1). In under ages 30 18 years, increased 9.0 % 12.0 %, respectively. This is so far largest multigene We confirmed as most frequently involved gene, but uncovered rarer genetic causes results may contribute better understanding landscape tumours help decide which include screening

Language: Английский

---

Therapeutic targeting of RNA for neurological and neuromuscular disease

Genes & Development, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 14, 2024

Neurological and neuromuscular diseases resulting from familial, sporadic, or de novo mutations have devasting personal, societal impacts. As the initial product of DNA transcription, RNA transcripts their associated ribonucleoprotein complexes provide attractive targets for modulation by increasing wild-type blocking mutant allele expression, thus relieving downstream pathological consequences. Therefore, it is unsurprising that many existing under-development therapeutics focused on targeting disease-associated as a frontline drug strategy these genetic disorders. This review focuses current range modalities using examples both dominant recessive neurological diseases.

Language: Английский

---

Low frequency of AIP mutations in patients with young-onset sporadic pituitary macroadenomas

Journal of Endocrinological Investigation, Journal Year: 2023, Volume and Issue: 46(11), P. 2299 - 2307

Published: May 7, 2023

Mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene cause familial isolated pituitary adenomas (FIPA). AIP mutations have also been found patients with apparently sporadic adenomas, particularly young large adenomas. The aim of this study was to determine frequency germline young-onset macroadenomas.The sequenced 218 Portuguese macroadenomas diagnosed before age 40 years.Heterozygous rare sequence variants were identified 18 (8.3%) patients. However, only four (1.8%) had pathogenic or likely variants. These consisted two already known (p.Arg81* and p.Leu115Trpfs*41) novel (p.Glu246*, p.Ser53Thrfs*36). All GH-secreting between ages 14 25 years. under 30 years 3.4% 5.0%, respectively.The cohort lower than other studies. Previous reports may overestimated contribution due inclusion genetic uncertain significance. identification expands spectrum causes help understand role molecular mechanisms underlying tumorigenesis.

Language: Английский

---

Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells

NAR Cancer, Journal Year: 2023, Volume and Issue: 5(3)

Published: June 9, 2023

Nonsense-mediated mRNA decay (NMD) is a eukaryotic RNA pathway with roles in cellular stress responses, differentiation, and viral defense. It functions both quality control post-transcriptional regulation of gene expression. NMD has also emerged as modulator cancer progression, although available evidence supports tumor suppressor pro-tumorigenic role, depending on the model. To further investigate role cancer, we knocked out factor SMG7 HT1080 human fibrosarcoma cell line, resulting suppression function. We then compared oncogenic properties parental SMG7-knockout, rescue line which re-introduced isoforms SMG7. tested effect drug inhibiting SMG1 to distinguish NMD-dependent effects from putative NMD-independent Using cell-based assays mouse xenograft model, showed that function severely compromises phenotype. Molecular analysis revealed strongly reduces matrix metalloprotease 9 (MMP9) expression MMP9 re-expression partially rescues Since promotes migration invasion, metastasis angiogenesis, its downregulation may contribute reduced tumorigenicity NMD-suppressed cells. Collectively, our results highlight potential value inhibition therapeutic approach.

Language: Английский

---

FMRP-mediated spatial regulation of physiologic NMD targets in neuronal cells

Genome biology, Journal Year: 2024, Volume and Issue: 25(1)

Published: Jan. 23, 2024

Abstract In non-polarized cells, nonsense-mediated mRNA decay (NMD) generally begins during the translation of newly synthesized mRNAs after are exported to cytoplasm. Binding FMRP translational repressor UPF1 on NMD targets mainly inhibits NMD. However, in polarized cells like neurons, additionally localizes cellular projections. Here, we review literature and evaluate available transcriptomic data conclude that, physiologic bound by is partially inhibited until localize There, displacement response signaling induces a burst protein synthesis followed rapid decay.

Language: Английский

---

Exon-junction complex association with stalled ribosomes and slow translation-independent disassembly

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 17, 2024

Abstract Exon junction complexes are deposited at exon-exon junctions during splicing. They primarily known to activate non-sense mediated degradation of transcripts harbouring premature stop codons before the last intron. According a popular model, exon-junction accompany mRNAs cytoplasm where first translating ribosome pushes them out. However, they also removed by uncharacterized, translation-independent mechanisms. Little is about kinetic and transcript specificity these processes. Here we tag core subunits with complementary split nanoluciferase fragments obtain sensitive quantitative assays for complex formation. Unexpectedly, form large stable mRNPs containing stalled ribosomes. Complex assembly disassembly rates determined after an arrest in transcription and/or translation. 85% newly disassembled translation-dependent mechanism. However as this process much faster than one, only 30% present cells steady state require translation disassembly. Deep RNA sequencing shows bias bound towards microtubule centrosome coding ones demonstrate that lifetimes transcript-specific. This study provides dynamic vision uncovers their unexpected association

Language: Английский

---

MAGED2 Is Required under Hypoxia for cAMP Signaling by Inhibiting MDM2-Dependent Endocytosis of G-Alpha-S

Cells, Journal Year: 2022, Volume and Issue: 11(16), P. 2546 - 2546

Published: Aug. 16, 2022

Mutations in MAGED2 cause transient Bartter syndrome characterized by severe renal salt wasting fetuses and infants, which leads to massive polyhydramnios causing preterm labor, extreme prematurity perinatal death. Notably, this condition resolves spontaneously parallel with developmental increase oxygenation. interacts G-alpha-S (Gαs). Given the role of Gαs activating adenylyl cyclase at plasma membrane consequently generating cAMP promote reabsorption via protein kinase A (PKA), we hypothesized that is required for signaling pathway under hypoxic conditions such as fetuses. Consistent that, both physical chemical hypoxia, knockdown (HEK293) cancer (HeLa) cell culture models caused internalization Gαs, was fully reversible upon reoxygenation. In contrast surface expression β2-adrenergic receptor, coupled not affected depletion, demonstrating specific regulation MAGED2. Importantly, due deficiency significantly reduced generation PKA activity. Interestingly, blocked preventing its endocytosis dynasore. E3 ubiquitin ligases, can be regulated MAGE-proteins, regulating endocytosis, assessed potential MDM2-dependent ubiquitination deficiency-induced hypoxia. Remarkably, MDM2 depletion or inhibition abolished Gαs-endocytosis following knockdown. Moreover, also mutation acceptor sites Gαs. Thus, reveal essential cAMP/PKA hypoxia specifically regulate blocking This may explain, least part, nature mutations opens new avenues therapy these patients.

Language: Английский

---

Identification of an evolutionary conserved binding motif responsible for the recruitment of NMD factors to the UPF1 helicase

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 3, 2024

Abstract The nonsense-mediated mRNA decay (NMD) pathway clears eukaryotic cells of mRNAs containing premature termination codons (PTC) or normal stop located in specific contexts. It therefore plays an important role gene expression regulation. precise molecular mechanism the NMD has long been considered to differ substantially from yeast metazoa, despite involvement universally conserved factors such as central ATP-dependent RNA-helicase Upf1. Here we describe crystal structure Upf1 bound its recently identified but yet uncharacterized partner Nmd4, show that Nmd4 stimulates ATPase activity and this interaction contributes elimination substrates. We also demonstrate a region critical for with is metazoan SMG6 protein, another major factor. involved UPF1, mutations affect levels endogenous human Our results support universal conservation eukaryotes.

Language: Английский

---