Biology subjects

Vanoye, C.

Publications and source records attributed to Vanoye, C..

3 recordsLinked to original sources

bioRxiv2026

Functional High Throughput Drug Screening Reveals Cyproheptadine as a Novel Treatment for LMNA -related Cardiomyopathy

ObjectivesTo define shared and variant-specific mechanisms underlying LMNA-associated dilated cardiomyopathy (DCM) and identify therapeutic candidates using human stem cell-based models. BackgroundVariants in the gene LMNA, encoding lamin A/C, cause 5-10% of dilated cardiomyopathies (DCM) and are strongly associated with heart failure and arrhythmias. Yet, the mechanisms by which LMNA variants drive disease and the distinction between shared and variant-specific phenotypes remain unclear. MethodsTo address this, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from six LMNA-DCM patients carrying three pathogenic variants (T150A, E381Afs*39, R527H) and from five healthy control patients. ResultsLMNA hiPSC-CMs exhibited nuclear membrane deformation, reduced beat rate, arrhythmias, and prolonged calcium transients. Transcriptomic and electrophysiological analyses revealed downregulation of cardiac genes and ion channels, with abnormal Ca{superscript 2} handling emerging as a shared disease mechanism. Leveraging a high-throughput functional assay, we performed an unbiased drug screen and identified cyproheptadine, an FDA-approved antihistamine, as the only compound to alleviate abnormal function across all LMNA variants. ConclusionOur findings reveal a shared disease mechanism across multiple LMNA variants driven by dysregulated Ca{superscript 2} handling. This work establishes a patient-specific drug discovery platform and identifies cyproheptadine as a promising therapeutic candidate for LMNA-associated dilated cardiomyopathy. HighlightsO_LIPatient-specific LMNA hiPSC-cardiomyocytes robustly recapitulate disease phenotypes, including nuclear defects, arrhythmias, and contractile dysfunction. C_LIO_LIDysregulated calcium handling emerges as a unifying mechanism driving pathology across distinct LMNA variants. C_LIO_LIVariant-resolved analysis reveals both shared and mutation-specific molecular and functional signatures. C_LIO_LIHigh-throughput screening identifies cyproheptadine as a potent, broadly effective rescue agent across all tested LMNA variants. C_LIO_LIThis work establishes a scalable precision medicine platform for rapid therapeutic discovery in inherited cardiomyopathies. C_LI

Cell Biology↗

bioRxiv2017

Mechanisms of KCNQ1 Channel Dysfunction in Long QT Syndrome Involving Voltage Sensor Domain Mutations

Loss-of-function (LOF) mutations in human KCNQ1 are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long-QT syndrome (LQTS). Hundreds of KCNQ1 mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. Here, we investigated the impact of 51 KCNQ1 variants located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding and structure. For each variant, the efficiency of trafficking to the plasma membrane, the impact of proteasome inhibition, and protein stability were assayed. The results of these experiments, combined with channel functional data, provided the basis for classifying each mutation into one of 6 mechanistic categories. More than half of the KCNQ1 LOF mutations destabilize the structure of the VSD, resulting in mistrafficking and degradation by the proteasome, an observation that underscores the growing appreciation that mutation-induced destabilization of membrane proteins may be a common human disease mechanism. Finally, we observed that 5 of the folding-defective LQTS mutants are located in the VSD S0 helix, where they interact with a number of other LOF mutation sites in other segments of the VSD. These observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilize the KCNQ1 VSD and, most likely, the corresponding domain of many other ion channels.\n\nOne Sentence SummaryLong QT syndrome-associated mutations in KCNQ1 most often destabilize the protein, leading to mistrafficking and degradation.

biochemistry↗

bioRxiv2017

High Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance

BackgroundThe explosive growth in known human gene variation presents enormous challenges to current approaches for variant classification that impact diagnosis and treatment of many genetic diseases. For disorders caused by mutations in cardiac ion channels, such as congenital long-QT syndrome (LQTS), in vitro electrophysiological evidence has high value in discriminating pathogenic from benign variants, but these data are often lacking because assays are cost-, time- and labor-intensive.\n\nMethods and ResultsWe implemented a strategy for performing high throughput, functional evaluations of ion channel variants that repurposed an automated electrophysiology platform developed previously for drug discovery. We demonstrated success of this approach by evaluating 78 variants in KCNQ1, a major LQTS gene. We benchmarked our results with traditional electrophysiological approaches and observed a high level of concordance. Our results provided functional data useful for classifying ~70% of previously unstudied KCNQ1 variants annotated with uninformative descriptions in the public database ClinVar. Further, we show that rare and ultra-rare KCNQ1 variants in the general population exhibit functional properties ranging from normal to severe loss-of-function indicating that allele frequency is not a reliable predictor of channel function.\n\nConclusionsOur results illustrate an efficient and high throughput paradigm linking genotype to function for a human cardiac channelopathy that will enable data-driven classification of large numbers of variants and create new opportunities for precision medicine.

genetics↗