RBFOX1 – Neurodevelopmental Disorder

RBFOX1 encodes the neuron-specific RNA-binding protein Fox-1, a critical regulator of alternative splicing in developing brain. Heterozygous loss-of-function variants in RBFOX1 have been repeatedly identified in patients with neurodevelopmental disorders (NDDs), characterized by global developmental delay, intellectual disability, speech impairment, and autistic features.

Genetic evidence comprises multiple independent case series: eight unrelated probands with small (<500 kb) intragenic deletions encompassing RBFOX1 identified by clinical array CGH ([PMID:22031302]), 14 pediatric patients with intragenic RBFOX1 deletions detected by chromosomal microarray ([PMID:23822903]), and six unrelated individuals harboring de novo RBFOX1 missense variants shown to cause loss of function in vitro ([PMID:37962958]). In a cohort of 1,800 NDD patients, RBFOX1 CNVs accounted for a significant proportion of pathogenic findings ([PMID:38674362]).

The variant spectrum is dominated by gene-disrupting events and missense changes. A representative missense allele, c.1057G>A (p.Gly353Ser), was associated with reduced systolic blood pressure and demonstrated splicing defects in cell assays ([PMID:28346479]). Haploinsufficiency is the prevailing mechanism, with no evidence for dominant-negative effects.

Functional studies confirm that RBFOX1 deficiency disrupts neuronal splicing programs. In vitro, tissue-dependent RBFOX1 isoforms bind the UGCAUG motif to regulate neural exon inclusion ([PMID:15824060]). In mouse corticogenesis, knockdown of the cytoplasmic isoform (Rbfox1-iso2) impairs radial migration, nucleokinesis, and dendritic arborization ([PMID:26500751]); similar defects occur upon silencing of the nuclear isoform (Rbfox1-iso1) ([PMID:27481563]).

Animal models recapitulate human phenotypes: rbfox1 loss-of-function zebrafish (rbfox1sa15940, rbfox1del19) exhibit hyperactivity, thigmotaxis, altered social behavior, and reduced freezing analogous to ASD-like traits ([PMID:36865197]). In Drosophila, splicing network perturbation involving Rbfox1 rescue of mushroom body defects supports a conserved hierarchy of splicing factors in neurodevelopment ([PMID:37962958]).

Integrating genetic and experimental data, RBFOX1 meets ClinGen criteria for a Strong gene-disease association in autosomal dominant NDDs. Haploinsufficiency leads to mis-splicing of neuronal transcripts and impaired cortical development. Key take-home: RBFOX1 genetic testing informs diagnosis of NDDs and guides future therapeutic targeting of splicing mechanisms.

References

• American journal of medical genetics. Part A • 2011 • Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders. PMID:22031302
• Molecular cytogenetics • 2013 • Intragenic deletion of RBFOX1 associated with neurodevelopmental/neuropsychiatric disorders and possibly other clinical presentations. PMID:23822903
• Genes • 2024 • Genetic Alterations in a Large Population of Italian Patients Affected by Neurodevelopmental Disorders. PMID:38674362
• The Journal of clinical investigation • 2024 • Spliceosome malfunction causes neurodevelopmental disorders with overlapping features. PMID:37962958
• Nucleic acids research • 2005 • Tissue-dependent isoforms of mammalian Fox-1 homologs are associated with tissue-specific splicing activities. PMID:15824060
• Molecular autism • 2015 • Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex. PMID:26500751
• Scientific reports • 2016 • Essential role of the nuclear isoform of RBFOX1, a candidate gene for autism spectrum disorders, in the brain development. PMID:27481563
• bioRxiv • 2023 • Pleiotropic contribution of rbfox1 to psychiatric and neurodevelopmental phenotypes in a zebrafish model. PMID:36865197
• PLoS genetics • 2017 • Rare variants in fox-1 homolog A (RBFOX1) are associated with lower blood pressure. PMID:28346479

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