Biology subjects

Quinodoz, M.

Publications and source records attributed to Quinodoz, M..

5 recordsLinked to original sources

bioRxiv2026

COQ8 chaperones coenzyme Q lipid intermediates through ATP-driven structural gating

Coenzyme Q biosynthesis requires the atypical kinase-like COQ8 proteins, whose ATPase activity streamlines the membrane-associated COQ metabolon, yet its molecular mechanism has remained unclear. Taking advantage of the tetrapod ancestral coenzyme Q biosynthetic machinery and liposomes mimicking the inner mitochondrial membrane, we show that COQ8A and COQ8B act as a streamlining factor for the coenzyme Q metabolon by engaging in loose protein-protein interactions and delivering insoluble biosynthetic intermediates. Structural bioinformatics and pathological-variant-driven mutagenesis reveal that coenzyme Q intermediates are recognized via their head-groups in a pocket whose access is gated by long-range conformational changes controlled by ATP hydrolysis. Finally, it is demonstrated that excess coenzyme Q suppresses binding of early-stage intermediates and thereby abolishes the streamlining effect of COQ8 on the metabolon. Together, these results support a model in which COQ8 functions as a biochemical coenzyme Q sensor that tunes coenzyme Q biosynthesis by coupling ATPase-driven intermediate chaperoning with feedback regulation by the final product. TeaserCOQ8 enhances coenzyme Q metabolic flux via ATP hydrolysis-driven chaperoning of biosynthetic intermediates.

biochemistry↗

bioRxiv2025

RetiGene, a comprehensive gene atlas for inherited retinal diseases (IRDs)

Inherited retinal diseases (IRDs) are rare disorders, typically presenting as Mendelian traits, that result in stationary or progressive visual impairment. They are characterized by extensive genetic heterogeneity, possibly the highest among all human genetic diseases, as well as diverse inheritance patterns. Despite advances in gene discovery, limited understanding of gene function and challenges in accurately interpreting variants continue to hinder both molecular diagnosis and genetic research in IRDs. One key problem is the absence of a comprehensive and widely accepted catalogue of disease genes, which would ensure consistent genetic testing and reliable molecular diagnoses. With the rapid pace of IRD gene discovery, gene catalogues require frequent validation and updates to remain clinically and scientifically useful. To address these gaps, we developed RetiGene, an expert-curated gene atlas that integrates variant data, bulk and single-cell RNA sequencing, and functional annotations. Through the integration of diverse data sources, RetiGene supports candidate gene prioritization, functional studies, and therapeutic development in IRDs.

genetics↗

bioRxiv2023

High-efficiency base editing for Stargardt disease in mice, non-human primates, and human retina tissue

Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector split-intein adenine base-editing strategy to correct the most common mutation in ABCA4 (c.5882G>A, p.G1961E). We optimized ABCA4 base editing in human models, including retinal organoids, iPSC-derived retinal pigment epithelial (RPE) cells, as well as adult human retinal- and RPE/choroid explants in vitro. The resulting gene therapy vectors achieved high levels of gene correction in mutation-carrying mice and in non-human primates, with an average editing of 37% of photoreceptors and 73% of RPE cells in vivo. The high editing rates in primates make way for precise and efficient gene editing in other neurodegenerative ocular diseases.

neuroscience↗

bioRxiv2020

CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels

CEP78 is a centrosomal protein implicated in ciliogenesis and ciliary length control, and mutations in the CEP78 gene cause retinal cone-rod dystrophy associated with hearing loss. However, the mechanism by which CEP78 affects cilia formation is unknown. Based on a recently discovered disease-causing CEP78 p.L150S mutation, we identified the disease-relevant interactome of CEP78. We confirmed that CEP78 interacts with the EDD1-DYRK2-DDB1VPRBP E3 ubiquitin ligase complex, which is involved in CP110 ubiquitination and degradation, and identified a novel interaction between CEP78 and CEP350 that is weakened by the CEP78L150S mutation. We show that CEP350 promotes centrosomal recruitment and stability of CEP78, which in turn leads to centrosomal recruitment of EDD1. Consistently, cells lacking CEP78 display significantly increased cellular and centrosomal levels of CP110, and depletion of CP110 in CEP78-deficient cells restored ciliation frequency to normal. We propose that CEP78 functions downstream of CEP350 to promote ciliogenesis by negatively regulating CP110 levels via an EDD1-dependent mechanism.

cell biology↗

bioRxiv2018

Frequent variants in the Japanese population determine quasi-Mendelian inheritance of rare retinal ciliopathy

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e. a 3.5-fold enrichment; p-value = 9.2x10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation, in trans with the Alu insertion, but might also cause disease in association with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

genomics↗