Sophie Saunier

Centriolar satellites are membrane-less organelles that store, modify and traffic proteins, in particular those of the centrosome and the primary cilium, and their deregulation is linked to ciliopathies, neurodevelopmental and neurodegenerative disorders. Satellite number, size, intensity and spatial distribution vary with cell type and cell state, yet satellites are usually quantified by a single readout, the pericentrosomal fluorescence intensity in maximum-projected images, which cannot distinguish changes in satellite number, size and position. Here we present SatelliteQ, an open-source Fiji and Python workflow for object-based quantification of satellites in 2D, 3D and time-lapse images. SatelliteQ segments satellites, detects centrosomes or primary cilia in the same cells, and reports satellite number, size, intensity, distance to the centrosome, shape and spatial distribution per satellite and per cell, with interactive graph and spatial viewers. Its measurements correlate closely with Imaris-based quantification; absolute values depend on segmentation settings and analysis mode, whereas the biological differences tested here were preserved across matched settings. Using SatelliteQ, we resolved distinct spatial signatures of satellite dispersal induced by microtubule depolymerization and by disruption of weak hydrophobic interactions, quantified differences between cell types and the scaling of satellite number with cell size, captured PCM1 granule dynamics in living cells, and compared satellite organization between ciliated and unciliated cells. Depletion of the ciliopathy-associated satellite protein CEP290 altered satellite abundance and pericentrosomal organization, while patient-derived cells carrying CEP290 mutations displayed divergent satellite phenotypes that were not explained by ciliation alone. SatelliteQ thus establishes satellite properties as a multidimensional cellular phenotype and provides an accessible framework for exploring satellites as an organelle-level readout in disease.

The primary cilium is a microtubule-based sensory organelle projecting from the plasma membrane of most mammalian cells. Genetic defects in ciliary components cause chronic kidney disease (CKD) characterized by heightened production of inflammatory and fibrogenic mediators by tubular epithelial cells. Yet, whether this reflects a physiological role of the primary cilium remains unknown. Here, we show that primary cilia on kidney tubular cells bind uropathogenic Escherichia coli and, in response to bacterial components, initiate a fibro-inflammatory program reminiscent of CKD. Integrating single-cell transcriptomics with conditional mouse models, we observed that epithelial cilia orchestrate a similar fibro-inflammatory response in the absence of infection during CKD. This convergence reveals a shared cilia-dependent signalling axis governing both host–pathogen responses and CKD progression. Mechanistically, cilia ablation selectively impairs tubular responses to ADP-heptose, a pathogen-associated molecular pattern that activates NF-κB via the cytosolic innate immune receptor ALPK1. In human kidney organoids, ADP-heptose induces robust fibro-inflammation, and genetic or pharmacological inhibition of ALPK1 attenuates this response in a rodent CKD model. Together, these findings identify primary cilia as central orchestrators of a fibro-inflammatory program linking pathogen detection to kidney disease progression.

Objectives: Rare diseases often require longitudinal monitoring to characterise progression, yet much clinical information remains locked in unstructured electronic health records (EHRs). Efficient recovery of such data is critical for accurate prognostic modelling and clinical trial preparation. We aimed to develop and evaluate a small language model (SLM)-based pipeline for extracting longitudinal information from French clinical notes of patients with rare kidney diseases. Methods: As a use case, we focused on serum creatinine, a key biomarker of kidney function. We analyzed 81 clinical notes comprising 200 measurements (triplet of date, value and unit). Four open-source SLMs (Mistral-7B, Llama-3.2-3B, Qwen3-4B, Qwen3-8B) were systematically tested with different prompting strategies in French and English. Outputs were post-processed to standardize formats and resolve inconsistencies, and performance was assessed across model size, prompting, language, and robustness to text duplication. Results: All SLMs extracted structured triplets, with F1-scores ranging from 0.519 to 0.928 (Qwen3-8B), outperforming the rule-based baseline. Larger models generally performed better, while prompting strategy and language had modest effects across models. SLMs also showed variable robustness to duplicated content common in real-world EHR notes. Discussion: Lightweight, locally deployable language models can accurately extract longitudinal biomarkers from unstructured clinical notes. Our findings highlight their practicality for rare diseases where data scarcity often limits task-specific model training. Conclusion: SLMs provide a privacy-preserving and resource-efficient solution for recovering longitudinal biomarker trajectories from unstructured notes, offering potential to advance real-world research and patient care in rare kidney diseases. 1) What is already known?: Longitudinal monitoring is essential in rare kidney diseases, yet key biomarker data are often locked in unstructured clinical notes. Large language models (LLMs) have shown strong performance in clinical text processing tasks but face major challenges related to privacy, computational cost, and implementation feasibility in healthcare settings. Small language models (SLMs) are emerging as lightweight, locally deployable alternatives whose potential for clinical applications is increasingly recognized. 2) What does this paper add?: This study provides the first real-world evaluation of SLMs for extracting longitudinal biomarker measurements in rare kidney disease cohorts. It introduces and validates an efficient extraction pipeline that combines document preselection, SLM prompting, and post-processing to accurately retrieve biomarker measurements from French clinical notes. The findings show that SLM-based extraction can help mitigate data scarcity in rare diseases, thereby improving prognosis modeling and supporting clinical research.

Primary cilia are tiny cellular protrusions of nearly every vertebrate cell controlling multiple cellular processes, such as proliferation, differentiation, migration etc. Their dysfunction results in severe human diseases collectively referred to as ciliopathies. Remarkably, many ciliopathies are associated with increased programmed cell death (PCD). However, it is largely unknown how primary cilia regulate PCD. In in vitro (murine and human cells) and in vivo ( Xenopus laevis and mouse) models, we observed elevated PCD in the absence of the ciliopathy protein RPGRIP1L. Mechanistically, our data elucidated that RPGRIP1L controls PCD by governing the activity of the ciliary proteasome. By using super-resolution microscopy, we first showed that the apoptosis inducer MOAP1 localises to primary cilia. Furthermore, our investigations revealed that RPGRIP1L controls PCD via the degradation of MOAP1 by the ciliary proteasome. Based on our finding that two more ciliopathy proteins, TCTN1 and CEP290, modulate PCD via regulating the activity of the ciliary proteasome, we suggest that the proteasomal degradation of MOAP1 represents a general mechanism by which primary cilia control PCD.

Background: Defects in photoreceptor ciliary function cause retinal ciliopathies, a major group of inherited blinding disorders. Current therapies are limited by extensive genetic heterogeneity, small patient populations, and high development costs, underscoring the need for mutation-agnostic strategies. This study investigates cAMP signaling modulation as a means to enhance ciliogenesis and preserve retinal structure and function in models of retinal ciliopathies. Methods: Taprenepag, a selective prostaglandin E₂ EP2 receptor agonist, was characterized for receptor specificity and downstream signaling. Its ability to enhance ciliogenesis was assessed by immunofluorescence microscopy in patient-derived urine-derived renal epithelial cells (URECs) carrying NPHP1 or CEP290 mutations and in dermal fibroblasts from CEP290 , BBS1 , and BBS10 patients. In CEP290-deficient cells, which exhibited a spectrum of baseline ciliary defects, taprenepag’s effect on ciliogenesis was compared with forskolin and cAMP analogs. Intracellular cAMP levels were measured by ELISA to confirm EP2-mediated signaling. In vivo efficacy was evaluated in Cep290 -deficient mice following systemic taprenepag administration, with retinal morphology assessed by histology and function by electroretinography. Statistical significance was determined using one- or two-way ANOVA with appropriate post hoc tests. Results: Taprenepag significantly enhanced ciliogenesis across all mutant cell types through EP2-mediated cAMP elevation, effectively bypassing the need for gene-specific correction. In severely cilia-depleted cells, elevated cAMP alleviated early ciliogenesis defects, acting upstream of axoneme assembly and intraflagellar transport, suggesting that spatially restricted EP2 signaling initiates cilium formation. In Cep290 -deficient mice, taprenepag promoted photoreceptor outer segment development, increased outer nuclear layer thickness, and partially restored retinal responses, indicating both structural preservation and functional rescue. Conclusions: EP2 receptor activation and subsequent cAMP signaling constitute a mutation-independent mechanism to promote ciliogenesis and neuroprotection in retinal ciliopathies. Taprenepag demonstrates broad therapeutic potential across diverse genetic backgrounds, supporting cAMP modulation as a promising avenue for treating inherited retinal degeneration. These findings provide a foundation for the preclinical advancement of EP2 agonists as mutation-agnostic therapies for retinal ciliopathies.

Key Points: Exome sequencing solved 26% of nephronophthisis cases, identifying nephropathy and extrarenal disease genes beyond classic ciliopathy panels. Exome sequencing uncovered GN and tubular nephropathy genes misdiagnosed as ciliopathy-associated nephropathy, underscoring diagnostic overlap in kidney diseases. Patients with nonciliary genetic variants may present with ciliopathy-like extrarenal symptoms, showing phenocopies in kidney ciliopathy diagnostics. Background: Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial kidney disease and a leading genetic cause of chronic kidney failure in children and young adults. As a ciliopathy, NPH is caused by biallelic variants in genes encoding proteins involved in the structure and function of primary cilia. The broad clinical spectrum of NPH results in a clinically and genetically heterogeneous disease, posing diagnostic challenges and leaving approximately 30% of cases unresolved with current gene panels. Methods: After targeted gene panel for ciliopathy-associated genes failed to identify diagnostic variants, exome sequencing (ES) was conducted on 42 unrelated index patients with a clinical diagnosis of NPH, defined as cystic nephropathy progressing to kidney failure within the first two decades of life, or by unspecific CKD accompanied by extrarenal features indicative of a ciliopathy. Results: Pathogenic or likely pathogenic variants were identified in 11 of the 42 patients (26%). Variants were detected in known nephropathy genes ( LAMB2 , COQ8B , COL4A3 , MUC1 ) and a multisystem disease gene with secondary kidney involvement ( AGXT ). In addition, ES elucidated deleterious variants explaining extrarenal phenotypes without corresponding kidney disease in six patients ( APTX , TUBB3 , DHX38 , IQCE, CRX , RPGR ). Variants of unknown significance were identified in three patients, while heterozygous variants in genes associated with recessive disease were observed in three others. A potential candidate gene for syndromic tubulointerstitial nephropathy, SSBP1 , was also identified, suggesting a novel pathway involving mitochondrial dysfunction. Conclusions: ES enabled the identification of pathogenic variants in known genes associated with kidney diseases, nonkidney conditions, and multisystem disorders with secondary kidney involvement, thereby improving diagnosis accuracy, even in incomplete or atypical cases, and guiding specific diagnostic and therapeutic approaches. The identification of SSBP1 in association with tubulointerstitial nephropathy may provide new insights into the pathogenesis of ciliopathies.

More than 4000 rare genetic diseases affect 1 in 16 people, yet ∼50% of patients remain undiagnosed after genetic testing. Identifying genotype-phenotype associations is challenged by small cohorts and high clinical and genetic heterogeneity. Rare variant burden tests increase statistical power in case-control studies, but are limited in rare disease research due to the lack of matched controls in retrospective studies. Recently proposed case-only aggregation tests assess the number of individuals with damaging variants under dominant or recessive models, but fail to capture additive effects, hypomorphic variants, or heterogeneous inheritance modes. Here, we present the Case-Only Burden Test (COBT), a gene-based burden test for case-only designs accounting for multiple variants per individual and their putative additive effects. COBT uses a Poisson model to test for excess variants in a gene compared to expectations from general population mutation rates. We validated the model’s assumptions and goodness-of-fit on a control cohort from the 1000 Genomes Project, where COBT showed low false-positive rates and outperformed alternative case-only tests. Applied to 478 ciliopathy patients, COBT re-identified known causal genes and highlighted novel candidate variants in unsolved cases. COBT enables gene discovery in case-only rare disease cohorts and is available at https://github.com/RausellLab/COBT .

Background: Primary cilia are sensory antennas that are present on the majority of quiescent vertebrate cells where they mediate key signaling during development and in response to environmental stimuli. Defects in primary cilia result in a group of heterogeneous inherited disorders with overlapping phenotypes, called ciliopathies. Nephronophthisis is an autosomal recessive tubulo-interstitial kidney ciliopathy with more than 25 identified genes called NPHP . Presently, no treatment exists beyond supportive care and kidney transplant, underscoring the need for novel therapies. Methods: Using a phenotypic screening approach in cultured cell lines, we previously identified prostaglandin analogues as candidate therapeutic molecules based on their ability to rescue ciliogenesis defects in kidney tubular cells from NPHP1 patients. Here, we have investigated the potential beneficial effects of ROCK inhibitors and Eupatilin, similarly identified by other groups in different NPHP contexts, in kidney cells from NPHP1 and IQCB1/NPHP5 patients as well as in a zebrafish NPHP mutant line ( traf3ip1/ift54 ). Results: Eupatilin partially rescued NPHP1 -associated ciliogenesis defects. Transcriptomic analyses pointed out that cell cycle progression was inhibited by Eupatilin, likely explaining its broad effects on cilia assembly. Interestingly, while ciliary defects also observed in NPHP5 patient cells were rescued by both prostaglandins and Eupatilin, only prostaglandin analogues were able to reduce pronephric cysts size in the used nphp zebrafish model. Conclusion: Our study indicates that these molecules can show beneficial effects across genetic contexts and shed light on their potential as therapeutic interventions for nephronophthisis.

Ciliopathies are a class of multi-systemic genetic diseases characterized by ciliary dysfunction. Here, we report a novel ANKS3 variant in patients with a renal ciliopathy known as nephronophthisis (NPH) associated with hepatic defects. ANKS3 is an ankyrin and sterile alpha motif domain-containing protein that interacts with many NPH proteins as well as with BICC1, an RNA-binding protein involved in renal cystic diseases. The pathogenic effect of the ANKS3 mutation was validated in the zebrafish mutant and knock-in rat model, the latter showing urine concentration defect and tubular dilatations similar to NPH patients. In addition, cilia morphology and function as well as epithelialization of kidney tubular cells was affected by loss or mutation of ANKS3 . Finally, our results evidenced that these classically renal ciliopathy-associated phenotypes were linked to the negative regulation of BICC1 by ANKS3 which binds to transcripts of the major NPH gene NPHP1 and mediates their decay through the AGO2-RISC complex and recruitment into P-bodies. Altogether, our findings suggest that the ANKS3/BICC1 complex is a key post-transcriptional regulator of NPHP1 transcript stability, providing another level of regulation of cilium biogenesis and kidney homeostasis, as well as an unusual mechanism leading to NPH-related ciliopathies.