Pathophysiological Heterogeneity of the BBSOA Neurodevelopmental Syndrome

Abstract

The formation and maturation of the human brain is regulated by highly coordinated developmental events, such as neural cell proliferation, migration and differentiation. Any impairment of these interconnected multi-factorial processes can affect brain structure and function and lead to distinctive neurodevelopmental disorders. Here, we review the pathophysiology of the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS; OMIM 615722; ORPHA 401777), a recently described monogenic neurodevelopmental syndrome caused by the haploinsufficiency of NR2F1 gene, a key transcriptional regulator of brain development. Although intellectual disability, developmental delay and visual impairment are arguably the most common symptoms affecting BBSOAS patients, multiple additional features are often reported, including epilepsy, autistic traits and hypotonia. The presence of specific symptoms and their variable level of severity might depend on still poorly characterized genotype-phenotype correlations. We begin with an overview of the several mutations of NR2F1 identified to date, then further focuses on the main pathological features of BBSOAS patients, providing evidence-whenever possible-for the existing genotype-phenotype correlations. On the clinical side, we lay out an up-to-date list of clinical examinations and therapeutic interventions recommended for children with BBSOAS. On the experimental side, we describe state-of-the-art in vivo and in vitro studies aiming at deciphering the role of mouse Nr2f1, in physiological conditions and in pathological contexts, underlying the BBSOAS features. Furthermore, by modeling distinct NR2F1 genetic alterations in terms of dimer formation and nuclear receptor binding efficiencies, we attempt to estimate the total amounts of functional NR2F1 acting in developing brain cells in normal and pathological conditions. Finally, using the NR2F1 gene and BBSOAS as a paradigm of monogenic rare neurodevelopmental disorder, we aim to set the path for future explorations of causative links between impaired brain development and the appearance of symptoms in human neurological syndromes.

Keywords: BBSOAS; NR2F1; clinical symptoms; genotype-phenotype correlation; haploinsufficiency; mouse models; neurodevelopmental disorder.

Figure 1

Schematic representations of NR2F1 gene localization, expression profile and pathogenic point variants. The human NR2F1 gene, located on chromosome 5 (region 5q14–q15), codes for a 3.824 base pairs (bp)-long transcript containing three distinct exons, translated into a 423 amino acid (aa)-long protein (Source: Human hg38 chr5:93583222-93594611 UCSC Genome Browser v427). The NR2F1 expression profile in different tissues and organs is shown as normalized transcript per million (nTPM). Source: human transcriptome dataset at Human Protein Atlas (HPA) (Query: ENSG00000175745-NR2F1). NR2F1 haploinsufficiency in BBOSAS patients is caused by gene deletion or by loss-of-function mutations affecting one allele. Small indels and point variants (black asterisks) tend to fall in the ATG starting codon (1), in the DBD (2) or in the LBD (3). Protein truncations (or frameshift variants followed by truncation at variable distance) are listed with a grey asterisk (4). All variants indicated by asterisks are also listed in the boxes, grouped by gene region or variant type. Whole-gene deletions, not shown here, are listed together with point variants in Table 1.

Figure 2

BBSOAS clinical spectrum. List of main BBSOAS symptoms and features, subdivided by affected systems. While developmental delay, intellectual disability and optic atrophy are the most common features (88%, 85.9% and 66.3% of patients, respectively), other symptoms are less common, such as CVI (44.6%), epilepsy (46.7%), ASD or autistic traits (39.1% and 14.1%, respectively), hearing impairment (11%) and hypotonia (62%). Abbreviations: ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CVI, cortical visual impairment; IQ, intelligence quotient.

Figure 3

Overview of structural and functional defects along the visual pathway in BBSOAS patients and corresponding Nr2f1 mutant mouse models. CVI and other visual impairments reported in BBSOAS patients (blue boxes) might build upon structural impairment affecting several structures in the visual system, such as the neural retina (NR), the optic disc (OD), the optic nerve (ON), the primary visual area of the neocortex (V1) and its connections to secondary associative areas. The use of Nr2f1 mutant mouse models (green boxes) have helped in elucidating the molecular, cellular and functional mechanisms that could potentially cause the defects observed in patients.

Figure 4

NR2F1 molecular functioning and dimer formation hypothetical predictions upon distinct genetic perturbations. Distinct deletions and mutations affecting NR2F1 genomic sequence (left column) could result in specific scenarios of impaired quantity and/or quality of NR2F1 homo- and heterodimers (central and right columns), possibly explaining a genotype–phenotype correlation. While decreased NR2F1 expression has been proven for some ATG point variants and for gene deletions, other scenarios—such as the dominant-negative effect of DBD- or LBD-mutated variants—are poorly understood to date. In a similar way, the possible consequences of the production of truncated NR2F1 forms are purely theoretical and will need further experimental assays to be confirmed and characterized. The exact 3D structure of nuclear receptor dimers and their formation rate, the identity of NR2F1 cofactors and the possible toxic effect of frameshift/truncated variants will require further studies. The asterisks indicate point mutations (color-coded following their genetic category), whereas stop symbols (in red and white) represent truncation sites.