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Models of Bosch-Boonstra-Schaaf optic atrophy syndrome reveal genotype-phenotype correlations in brain structure and behavior

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare, autosomal dominant neurodevelopmental disorder caused by pathogenic variants in NR2F1, characterized by developmental delay, intellectual disability, optic nerve anomalies and autism spectrum disorder. Most pathogenic variants cluster...

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Main Authors: Maaß, Johann (Author) , Kamionek, Dominik (Author) , Mantilleri, Annabelle (Author) , Theiß, Susanne (Author) , Dötsch, Laura (Author) , Franke, Felix (Author) , Schubert, Tim (Author) , Scheck, Jonas (Author) , Pitzer, Claudia (Author) , Piovani, Paolo (Author) , Bertacchi, Michele (Author) , Deschaux, Olivier (Author) , Singh, Anubhav (Author) , Chen, Chun-An (Author) , Fröhlich, Henning (Author) , Studer, Michèle (Author) , Schaaf, Christian P. (Author)
Format: Article (Journal)
Language:English
Published: 22 September 2025
In: Disease models & mechanisms
Year: 2025, Volume: 18, Issue: 10, Pages: 1-14
ISSN:1754-8411
DOI:10.1242/dmm.052426
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1242/dmm.052426
Verlag, kostenfrei, Volltext: https://journals.biologists.com/dmm/article/18/10/dmm052426/369253/Models-of-Bosch-Boonstra-Schaaf-optic-atrophy
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Author Notes:Johann G. Maass, Dominik Kamionek, Annabelle Mantilleri, Susanne Theiss, Laura Dötsch, Felix Franke, Tim Schubert, Jonas G. Scheck, Claudia Pitzer, Paolo Piovani, Michele Bertacchi, Olivier Deschaux, Anubhav Singh, Chun-An Chen, Henning Fröhlich, Michèle Studer and Christian P. Schaaf
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Summary:Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare, autosomal dominant neurodevelopmental disorder caused by pathogenic variants in NR2F1, characterized by developmental delay, intellectual disability, optic nerve anomalies and autism spectrum disorder. Most pathogenic variants cluster within the highly conserved DNA-binding domain (DBD) or ligand-binding domain (LBD) of NR2F1 and are associated with variable clinical severity, suggesting a genotype-phenotype correlation. Although previous mouse models have provided important insights, comprehensive behavioral characterization remains limited. Here, we present two novel BBSOAS mouse models harboring patient-specific variants in the DBD (Nr2f1+/R139L) and LBD (Nr2f1+/E397*), alongside the established Nr2f1+/− model. We analyzed brain morphology and behavior to further expand the murine phenotype and investigate the genotype-phenotype correlation. We demonstrate that these models recapitulate key aspects of the BBSOAS phenotype, including deficits in cognition, social communication and motor function, and that the presence and severity of behavioral abnormalities are dependent on variant type. Our findings provide new evidence for a genotype-phenotype correlation associated with domain-specific NR2F1 variants and establish a robust platform for future mechanistic and therapeutic studies.
Item Description:Gesehen am 05.03.2026
Physical Description:Online Resource
ISSN:1754-8411
DOI:10.1242/dmm.052426

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