Xavier Altafaj
University of Barcelona, Spain
Title
Comprehensive delineation and precision medicine of GRIN-related neurodevelopmental disorders, a primary disturbance of the NMDA receptor
Abstract
Glutamate is the main excitatory amino acid neurotransmitter in brain, playing a crucial role in neurogenesis, neuronal differentiation, synaptic plasticity and brain wiring processes. Glutamatergic neurotansmission disturbance can result from primary de novo mutations of GRIN genes, encoding for the N-methyl-D-Aspartate receptor (NMDAR) subunits. These rare autosomic dominant conditions cause severe neurodevelopmental encephalopathies namely GRIN-related disorders (GRD), displaying a clinical spectrum including intellectual disability, hypotonia, communication deficits, motor impairment, epilepsy and gastro-intestinal alterations. GRD (GRDs) clinical symptoms are gene- and amino acid position-dependent. Accordingly, as for other channelopathies, the functional annotation of GRIN de novo variants (DNVs) is critical i) to understand GRD pathophysiology, ii) to evaluate potential therapeutic strategies and iii) and to define personalised therapeutic approaches. During the last years we have created a multi-angled GRIN cluster initiative, merging computational, experimental, translational, and clinical neuroscience methodologies. Bioinformatic analysis allowed to build-up a comprehensive and specific GRIN variants database compiling genetic, structural, functional and clinical GRIN variants annotations. Further, this database allowed to define a superimposition structural algorithm that drastically increased GRIN variants annotations with a high predictive likelihood ultimately accelerating GRIN variants functional annotations. Together with the computational tools, an experimental pipeline has been established, allowing to annotate GRIN-orphan variants and to stratify them into loss-, gain-of-function (LoF, GoF, respectively) or complex outcomes. Further, we evaluated and experimentally demonstrated the potential therapeutic benefit of nutraceutical interventions (e.g. L-serine, polyamines) for the rescue of LoF GRIN variants. Importantly, these findings have been translated to the clinical practice, with an amelioration of motor and communicative skills observed in a proof of concept study, and are currently the object of the first reported GRD clinical trial.
Biosketch
After obtaining Molecular Biology degree (University of Barcelona, 1997), he performed a Functional Genomics study of Down syndrome (PhD degree Univ. Barcelona, 2002), and moved to the "Calcium channels: Functions and Pathology" Unit (CEA-INSERM, France, 2002-2006), where he studied the crosstalk between the plasma membrane DHPR and the ER-spanning Ryanodine receptor (RyR). Afterwards, he joined Dr. Fillat lab (2006-2011, Center for Genomic Research, Barcelona) and developed gene therapy strategies for Down syndrome models, while starting to study ionotropic glutamate receptors (iGluRs) in neurological conditions. His laboratory "Neurobiology of ionotropic Glutamate receptors in health and disease" (Dept. Biomedicine, Fac. Medicine, Univ. Barcelona, Spain) is focused to study the physiology of NMDA-type iGluRs and to unveil the molecular and cellular mechanisms bridging the gap between glutamate receptor dysfunction and neurological diseases. In particular, the main research line of his laboratory interest is the functional evaluation, stratification and development of precision therapies for pediatric encephalopathies resulting from de novo mutations affecting the NMDA receptor.