PEREZ PALMA, EDUARDO ESTEBAN
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PEREZ PALMA, EDUARDO ESTEBAN
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eduardoperez@udd.cl
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Scopus Author ID
55981322300

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2024 2024 2023 2023 2022 2022 2021 2021 0 0 2 2 4 4 6 6 8 8 10 10 12 12

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GRIN Portal: An Interactive Web Application Exploring GRIN Genes and Related Disorders

2023 , PEREZ PALMA, EDUARDO ESTEBAN , Klöckner, C , Brünger, T , Krey, I , Macnee, M , Myers, SJ , Yuan, HJ , Stefanski, A , May, P , Isabel M J Sargent , Park, K , Ramsey, AJ , Benke, T , Traynelis, SF , Lal, D , Lemke, J

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Delineation of functionally essential protein regions for 242 neurodevelopmental genes

2022 , Sumaiya Iqbal , Tobias Brünger , PEREZ PALMA, EDUARDO ESTEBAN , Marie Macnee , Andreas Brunklaus , Mark J Daly , Arthur J Campbell , David Hoksza , Patrick May , Dennis Lal , Lorena Diaz

Abstract Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are ‘variants of uncertain significance’. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can ‘tolerate’ missense variants and which ones are ‘essential’ and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants. We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including >360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients. In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14 377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute.org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.

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Molecular dynamics simulations reveal molecular mechanisms for the gain and loss of function effects of four SCN2A variants

2024 , PEREZ PALMA, EDUARDO ESTEBAN , Nisha Bhattarai , Ludovica Montanucci , Bruenger, Tobias , Martin, William , Smith, Iris N. , Cheng, Feixiong , Charis Eng , Helbig, Ingo , Moller, Rikkie S , Andreas Brunklaus , Stephanie Schorge , Dennis Lal

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Gain-of-function SCN1A variants cause spectrum of early onset epileptic encephalopathies that respond to sodium channel blocking therapies

2022 , PEREZ PALMA, EDUARDO ESTEBAN

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Comparison of variant effects in SCN-gene paralogs predict function across sodium channelopathies

2022 , PEREZ PALMA, EDUARDO ESTEBAN

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Dataset - Delineation of functionally essential protein regions for 242 neurodevelopmental genes

2022 , PEREZ PALMA, EDUARDO ESTEBAN

Neurodevelopmental disorders (NDDs) are a heterogeneous group of conditions involving various forms of disruption to brain development. Over hundreds of genes have been found to be associated with NDDs thus far. However, NDDs are complex and mutations in NDD associated genes are not straightforward to conceptualize at the molecular level, for which three-dimensional (3D) structures of proteins provide an informative mean. Here, we present the ES-NDD a tool that provides access to the aggregation of >470 experimentally and computationally modeled 3D monomeric structures as well as multimeric protein complexes and their characterization using a consensus approach to identity Essential3D sites are conserved across human paralogs. With ES-NDD a user is able to interactively explore 14, 377 Essential3D sites, that are paralog conserved, population constraint and enriched for pathogenic variants in the 3D structures, in the context of 71,479 population variants aggregated from gnomAD, 7,463 pathogenic (likely-pathogenic) variants from ClinVar and HGMD as well as functional and domain annotations from Uniprot.

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Dataset - Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes

2022 , PEREZ PALMA, EDUARDO ESTEBAN

Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. Consequently, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated. We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion channel families. We collected and curated 3,049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12,546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures.

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Dataset - Gene variant effects across sodium channelopathies predict function and guide precision therapy

2022 , PEREZ PALMA, EDUARDO ESTEBAN

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Dataset - Identification and quantification of oligogenic loss-of-function disorders

2021 , PEREZ PALMA, EDUARDO ESTEBAN

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Structural mapping of GABRB3 variants reveals genotype–phenotype correlations

2022 , Katrine M. Johannesen , Sumaiya Iqbal , Milena Guazzi , Nazanin A. Mohammadi , PEREZ PALMA, EDUARDO ESTEBAN , Elise Schaefer , Anne De Saint Martin , Marie Therese Abiwarde , Amy McTague , Roser Pons , Amelie Piton , Manju A. Kurian , Gautam Ambegaonkar , Helen Firth , Alba Sanchis-Juan , Marie Deprez , Katrien Jansen , Liesbeth De Waele , Eva H. Briltra , Nienke E. Verbeek , Marjan van Kempen , Walid Fazeli , Pasquale Striano , Federico Zara , Gerhard Visser , Hilde M.H. Braakman , Martin Haeusler , Miriam Elbracht , Ulvi Vaher , Thomas Smol , Johannes R. Lemke , Konrad Platzer , Joanna Kennedy , Karl Martin Klein , Ping Yee Billie Au , Kimberly Smyth , Julie Kaplan , Morgan Thomas , Malin K. Dewenter , Argirios Dinopoulos , Arthur J. Campbell , Dennis Lal , Damien Lederer , Vivian W.Y. Liao , Philip K. Ahring , Rikke S. Møller , Elena Gardella

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