Translational Research Investigating the Phenotypes of Bosch-Boonstra-Schaaf Optic Atrophy Syndrome

• Applicant: Professor Dr. Christian Schaaf
• Subject Area: Human Genetics
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 532002382

The nuclear hormone receptor and transcriptional regulator NR2F1 plays an important role in the development of the central nervous system, particularly in cell differentiation and neurogenesis. Pathogenic variants of NR2F1 cause Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS, OMIM #615722), an autosomal dominant neurodevelopmental disorder (NDD), characterized by optic atrophy, intellectual disability, autism spectrum disorder, hypotonia, and other neurological symptoms. Genotype-phenotype correlations have been described in human patients with BBSOAS, with individuals carrying missense variants in the DNA-binding domain (DBD) of the gene manifesting a more severe phenotype than those with loss-of-function (LOF) variants or variants in the ligand-binding domain (LBD). Because NR2F1 can act either as a homodimer or as a heterodimer with other co-factors, a dominant-negative effect has been proposed as the underlying pathomechanism for the severity of DBD or LBD variants. In this project, we propose to dissect the consequences and pathophysiological mechanisms of NR2F1 variants by (i) deciphering morphological and behavioral aspects of mouse models carrying human variants, and (ii) analyzing state-of-the-art genomic data from distinct mouse brain regions. We believe that this study will help to understand the phenotypic heterogeneity of patients, an important issue in clinical diagnosis, and unveil novel pathophysiological mechanisms common to NDDs. Overall, our goal is to contribute to our understanding of the genetic basis and pathophysiological mechanisms of BBSOAS, a newly emerging neurodevelopmental disorder that shares similarities with other complex and poorly understood diseases occurring during neural development. We anticipate that this will lead to a better understanding not only of the impact of NR2F1 variants in brain malformations, but also of downstream targets and pathways, providing insight into NR2F1’s key role during brain development more generally. Our work promises to establish models and identify key phenotypes that can then be used for future studies of therapeutic intervention.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Henning Fröhlich, Ph.D.