Neurogenomics Conference

Multiscale Insights into BBSOAS: Linking NR2F1 Mutations to Brain Development and Mitochondrial Dysfunction

19 May 2025, 18:30

3h

Board: 67

Poster presentation Poster Session

Speaker

MICHELE STUDER (Institut de Biologie Valrose - University Côte d'Azur)

Description

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS; OMIM 615722) is a rare neurodevelopmental disorder caused by mutations in NR2F1, a transcriptional regulator essential for brain and visual system development. Patients display a broad clinical spectrum—including intellectual disability, optic atrophy, autistic traits, and hypotonia—reflecting NR2F1 pleiotropic roles and suggesting genotype-phenotype correlations. Most mutations lead to haploinsufficiency or dominant-negative effects that impair NR2F1 transcriptional activity.

To uncover the molecular underpinnings of BBSOAS, we applied a multidisciplinary approach combining structural bioinformatics, genetic manipulation, patient-derived 3D cerebral organoids, animal models, imaging, and -omics analyses. We first characterized how specific NR2F1 point mutations alter protein structure, DNA binding, and localization, linking these defects to cortical malformations in mouse models and clinical neuroimaging. These studies highlight region-specific roles for NR2F1 in regulating neural stem cell maintenance and cortical folding.

In parallel, we identified a novel role for NR2F1 in mitochondrial regulation. Transcriptomic and proteomic profiling revealed that NR2F1 controls a network of nuclear-encoded mitochondrial genes, affecting mitochondrial mass and morphology. In Nr2f1-heterozygous mice, we observed significant disruption of mitochondrial pathways and reduced levels of key mitochondrial proteins in the brain. We are now extending these findings to human iPSC-derived telencephalic neurons. Preliminary imaging data suggest increased mitochondrial fragmentation in NR2F1-deficient human neurons, pointing to mitochondrial dysfunction as a key pathological mechanism in BBSOAS.

Altogether, our work shows that NR2F1 orchestrates both developmental and metabolic programs, with its dysfunction leading to impaired cortical architecture and mitochondrial homeostasis. This integrative framework advances our understanding of BBSOAS pathophysiology and supports the development of genotype-driven therapeutic strategies.