Analysis of the molecular profile of in vitro neuronal models of rare neurodevelopmental syndromes associated with the GRIN2A gene

• Grant number: 24/05023-3
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2024
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Sergio Tufik
• Grantee: Pedro Antonio Esteves Guerreiro
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Sleep disturbances in individuals with neurodevelopmental disorders are highly frequent, affecting up to 86% of patients. There is an overlap between the genetic factors that increase risk for both NDDs and sleep disturbances, indicating a common molecular root for this comorbidity. The GRIN2A gene encodes a subunit of NMDA receptors, glutamate- and voltage-dependent ion channels in glutamatergic neurons. Some rare variants in this gene were associated with the Landau-Kleffner syndrome, in which patients frequently have NDDs and epileptic encephalopathies (EE). Patients with these phenotypes that undergo electroencephalography display an atypical pattern of electrical activity spikes during slow-wave sleep. The consequences of such spikes are still unknown, as well as their possible effect on patients' sleep. This study aims to detect which biological pathways may be compromised by the gain or loss of function of GRIN2A caused by pathogenic variants found in EE patients, as well as assay the impacts of these variants in the transcription of other genes. We will assay the transcriptional profile of human induced pluripotent stem-cell (hiPSC) lines harboring deletions of the GRIN2A gene, as well as missense variants, by utilizing RNA-seq and ATAC-seq techniques. The gathered data will be integrated and compared with bioinformatics techniques, providing context-rich information on the molecular consequences of edits. Our findings will shed light on the molecular mechanisms involved in the etiology of NDDs and EEs, providing a basis for future research and possible pharmacological targets targeting the enriched pathways.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MOSINI, AMANDA CRISTINA; MOYSES-OLIVEIRA, MARIANA; DE ARAUJO, JESSICA NAYARA GOES; GUERREIRO, PEDRO; CUNHA, LAIS; ZAMARIOLLI, MALU; XAVIER, SANDRA DORIA; BALBUENO, BIANCA; DE MELLO, CLAUDIA BERLIM; MOREIRA, GUSTAVO ANTONIO; et al. Sleep complaints in individuals with SYNGAP1-associated syndrome. Sleep Medicine, v. 126, p. 8-pg., 2024-12-28. (21/09089-0, 20/13467-8, 24/05023-3, 23/14935-3, 23/09760-0)