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From misclassified AIP variant to carney complex: a case report and retrospective evaluation of PRKAR1A in pituitary tumor predisposition
No full textInternational audienceCarney Complex (CNC) is a rare multiple endocrine neoplasia syndrome, due to PRKAR1A mutation, that causes GH-secreting pituitary adenomas (PA) in 10% of patients. PRKAR1A is not currently analyzed in patients with isolated spo- radic or familial PA, in contrast to MEN1 or AIP. Objective We report the case of a young man diagnosed with a PA at age 21 during melanoma follow-up, with a family history of PA. He was initially misdiagnosed with FIPA due to a misclassified AIP mutation, before a final diagnosis of CNC was established. We subsequently retrospectively analysed PRKAR1A in a cohort of patients with PA to assess the relevance of includingPRKAR1A in PA predisposition gene panels. Methods After AIP variant reclassification and whole genome analysis of the patient, we performed a retrospective analysis of the genetic and clinical data of patients who underwent germline genetic testing for hereditary predisposition to PA. Results Two hundred and twenty patients were included, of whom 16 (7.3%) had a family history of PA, 162 (72.7%) had macro-PA, and 54 (24.6%) had GH- or GH/PRL-secreting PA. Four patients (1.8%) carried pathogenic variants in AIP or MEN1, but none in PRKAR1A. Conclusion This case underscores the importance of periodically reassessing genetic variants, as reclassification can signifi- cantly impact patient management. It also highlights the clinical variability of CNC and the need to screen for CNC features in young patients with acromegaly. Further research is warranted to determine the value ofPRKAR1A testing in isolatedGH- and GH/PRL-secreting PA
Long‐read sequencing of recurrent FGF12 duplications in epilepsy: Insights into structural mechanisms and aberrant isoforms
No full textInternational audienceObjective Fibroblast growth factor 12 ( FGF12 ), a member of the fibroblast homologous factor family, plays a key role in the modulation of voltage‐gated sodium (Nav) channels. Pathogenic variants in the FGF12 gene leading to a gain‐of‐function mechanism and partial duplication encompassing the FGF12 gene leading to a loss‐of‐function mechanism are associated with developmental and epileptic encephalopathy (DEE), characterized by developmental delay, intellectual disability, ataxia, and drug‐resistant epilepsy. We report two patients with DEE harboring de novo recurrent intragenic duplications of FGF12 identified by long‐read sequencing (LRS). Methods We applied LRS to the DNA and cDNA of patients with FGF12 duplication to fully characterize the DNA's structural organization and its transcriptional consequences. Additionally, we reanalyzed electroencephalographic (EEG) data from patients at different timepoints to identify phenotypical specificities and refine the electroclinical spectrum. Results These duplications, spanning approximately 536 kbp, were mediated by nonallelic homologous recombination between L1PA2 elements (LINE‐1 Primate‐specific subfamily A, number 2). cDNA analysis revealed aberrant transcripts, one predicted to encode an elongated FGF12 protein and another leading to premature termination. Both patients shared overlapping clinical features, including postepilepsy onset regression, global developmental delay, and ataxia. EEG studies revealed a marked early encephalopathic pattern with disorganized and high‐voltage slow background activity with multifocal spikes at onset evolving later into subcontinuous generalized spike and wave activation. Significance Our findings are consistent with previous reports linking structural variants to functional disruption, suggesting impaired Nav channel activity due to a shift in inactivation to hyperpolarized potential, leading to a loss‐of‐function effect. These findings underscore the utility of LRS for DNA and cDNA analysis in resolving structural variants and expanding the electroclinical spectrum of patients with FGF12 duplications
French perspectives on the 2025 ESC/EACTS guidelines for valvular heart disease
No full textInternational audienc
Leptospirosis seroprevalence and exposure factors in three informal settlements of French Guiana: An opportunistic survey
No full textInternational audienceBackgroundLeptospirosis is a zoonotic disease of increasing importance in French Guiana. It particularly affects subjects living in precarious conditions. We aimed to determine the seroprevalence and the risk of exposure to leptospirosis among inhabitants of three informal settlements in French Guiana.MethodsA serological investigation was conducted in 2022 in three informal settlements in the area of Cayenne, the main city of French Guiana. Leptospirosis exposure factors were assessed in volunteers aged > 15 through a standardized questionnaire. Leptospirosis seroprevalence was evaluated with Microscopic Agglutination Test (MAT) using 17 pathogenic Leptospira antigens with a reactivity threshold of 1:100.ResultsIn 266 participants, median [IQR] age was 42 [34–52] and male to female sex ratio was 0.9. Most participants were migrants (96%), mainly from Haiti (83%), and lived in the study area for at least 2 years (82%). Household rodent exposure (89%) and use of other water sources than collective standpoint (92%) were common. An at-risk occupation was reported for 68% of working participants. Leptospirosis seroprevalence was 7.5% (95% CI [4.7-11.4]) with Ballum and Icterohaemorrhagiae as the main serogroups. Foot skin exposure in wet environments was associated with reactive serum (OR 7.6, 95% CI [1.1 - 326.7]).ConclusionDespite a high theoretical risk of leptospirosis exposure among informal settlements inhabitants, only a few participants were seroreactive for Leptospira. This may suggest that despite at-risk exposures the effective transmission of leptospirosis remains limited within the study area. Broader serological surveys and environmental studies should clarify the areas of at-risk leptospirosis transmission in French Guiana
Assessment of measurable residual disease in ovarian tissue collected for fertility preservation in patients in remission from acute myeloid leukaemia: A pilot study
No full textInternational audienceSummary Allogeneic haematopoietic stem cell transplantation (ASCT) is a curative treatment for acute myeloid leukaemia (AML) but carries a high risk of gonadotoxicity. Ovarian tissue cryopreservation (OTC) offers a fertility preservation option, yet its safety in AML remains uncertain due to the risk of leukaemic cell reintroduction. The FERTILAM pilot study evaluated measurable residual disease (MRD) in ovarian tissue collected at complete remission (CR) from nine AML patients undergoing OTC before ASCT. MRD was assessed using patient‐specific clonal markers via droplet digital polymerase chain reaction on DNA and RNA from bone marrow (BM), ovarian cortex and medulla. At CR, MRD‐DNA was detected in ovarian cortex of four of nine patients, all with concurrent MRD positivity in BM. Three patients were negative in both BM and ovarian tissue. Paired cortex/medulla analyses showed concordant MRD‐DNA results in five of six patients. BM MRD‐RNA and MRD‐DNA were fully concordant, whereas two discrepancies were observed between MRD‐DNA and MRD‐RNA in ovarian tissue. These findings suggest potential leukaemic cell persistence in ovarian tissue despite CR and highlight the need for sensitive molecular assays to assess safety prior to ovarian tissue transplantation
Evaluating experimental design to sample mosquitoes
No full textInternational audienceMosquito study is crucial for public health, research, and vector control. We evaluated four understudied aspects of experimental design: (i) global efficiency of trapping devices—BG-Sentinel (BG) vs. CDC light traps (LT), (ii) temporal efficiency over a three-day sampling period, (iii) the impact of sampling duration on vector presence and abundance assessments, and (iv) site visit frequency for biodiversity surveys. Both traps were deployed across 10 Cambodian provinces, with collections conducted every 24 h over three-day periods from 2019 to 2021. A total of 1992 collections yielded 181,798 mosquitoes spanning 153 identified species. Using a hurdle generalized linear mixed model to address overdispersion and zero inflation, we found that 21 of 54 studied species showed a preference for one of the trapping device: LT captured 15 species more efficiently, while six species preferred BG. Anthropophilic vectors such as Aedes aegypti and Aedes albopictus were more attracted to BG, whereas LT captured higher species richness and zoophilic vectors. For six of 13 primary vector species, we showed that the capture efficiency declines from day one to day three on a three days sampling period. However, annual trends in presence and abundance remained consistent regardless of whether sampling lasted one, two, or three days. Finally, we quantified the probability of collecting a new species during subsequent visits, showing that this probability declines with visit sampling effort at rates dependent on trap type and sampling days duration. These findings provide empirical guidelines for optimizing mosquito surveillance strategies based on study objectives
Characterization of the Regulatory AAA-ATPase Subunit Rpt3 in Plasmodium berghei as an Activator of Protein Phosphatase 1
No full textInternational audienceThe 26S proteasome is the main proteolytic machinery involved in protein degradation, thereby contributing to the homeostasis and stress response of eukaryotic cells. This macromolecular complex consists of a 20S core particle assembled with one or two 19S regulatory particles. Here, we describe the Plasmodium berghei (Pb) proteasome AAA-ATPase regulatory subunit Rpt3 and demonstrate its binding to the Protein Phosphatase 1 catalytic subunit (PP1c), which is one of the major and essential parasite phosphatases. The PbRpt3 protein enhances the activity of PP1c both in vitro and in a Xenopus oocyte heterologous model. Further investigation of this model suggests that the PbRpt3-PP1c interaction may occur outside of the proteasome, and it reveals that the RVxF motifs of PbRpt3 are involved in its binding and regulatory function. Moreover, the ATP-binding capacity of PbRpt3 may also contribute to its phosphatase regulatory activity. In the parasite, reverse genetic studies suggest an essential role for PbRpt3 during erythrocytic cycle of P. berghei, and an interactome analysis confirmed that PbRpt3 belongs to the 19S regulatory particle of the proteasome and may interact with proteins previously shown to be involved in phospholipid binding
T cell memory response to MPXV infection exhibits greater effector function and migratory potential compared to MVA-BN vaccination
No full textInternational audienceAbstract In 2022, a global mpox outbreak occurred, and remains a concern today. The T cell memory response to MPXV (monkeypox virus) infection has not been fully investigated. In this study, we evaluate this response in convalescent and MVA-BN (Modified Vaccinia Ankara - Bavarian Nordic) vaccinated individuals using VACV-infected cells. Strong CD8 + and CD4 + T cell responses are observed, and T cell responses are biased towards viral early expressed proteins. We identify seven immunodominant HLA-A*02:01 restricted MPXV-specific epitopes and focus our detailed phenotypic and scRNAseq analysis on the immunodominant HLA-A*02:01-G5R 18-26 -specific CD8 + T cell response. While tetramer + CD8 + T cells share similar differentiation and activation phenotypes, T cells from convalescent individuals show greater cytotoxicity, migratory potential to site of infection and TCR clonal expansion. Our data suggest that effective functional profiles of MPXV-specific memory T cells induced by Mpox infection may have an implication on the long-term protective responses to future infection
Phylogenetic analysis of enteroviruses from non-human primates reveals two new species within the genus Enterovirus
No full textLIBX-A401: A Novel Selective Inhibitor of Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) and Its Binding Mode.
No full textInternational audienceAcyl-coenzyme A synthetase long-chain family member 4 (ACSL4), a pivotal enzyme in lipid metabolism, has emerged as a therapeutic target for ferroptosis-related conditions and cancer. However, its reference inhibitor, rosiglitazone, has off-target activity on peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of lipid homeostasis. Here, the discovery of LIBX-A401, a potent ACSL4 inhibitor derived from rosiglitazone devoid of PPARγ activity, is reported. Its binding to ACSL4 is ATP-dependent, stabilizing the C-terminal domain and altering the fatty acid gate region, as shown by Hydrogen-Deuterium Exchange Mass Spectrometry. Photoaffinity labeling identified A329 within the fatty acid binding site, while molecular dynamics and mutagenesis highlighted Q302 as critical for LIBX-A401 binding. LIBX-A401 exhibits anti-ferroptotic properties in cells, supported by target engagement. These findings establish LIBX-A401 as a valuable tool to study ACSL4 in ferroptosis and cancer, while its elucidated binding mode paves the way for the rational design of improved inhibitors