Dominant-negative mutations inCBX1cause a neurodevelopmental disorder

Abstract

Abstract Purpose This study aimed to establish variants in CBX1 , encoding heterochromatin protein 1β (HP1β), as a cause of a novel syndromic neurodevelopmental disorder. Methods Patients with CBX1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. To investigate the pathogenicity of identified variants, we performed in vitro cellular assays, neurobehavioral and cytological analyses of neuronal cells obtained from newly generated Cbx1 mutant mouse lines. Results In three unrelated individuals with developmental delay, hypotonia, and autistic features, we identified heterozygous de novo variants in CBX1 . The identified variants were in the chromodomain, the functional domain of HP1 β, which mediates interactions with chromatin. Cbx1 chromodomain mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Cytological and chromatin immunoprecipitation experiments confirmed the reduction of mutant HP1β binding to heterochromatin, while HP1β interactome analysis demonstrated that the majority of HP1β-interacting proteins remained unchanged between the wild-type and mutant HP1β. Conclusion These collective findings confirm the role of CBX1 in developmental disabilities through the disruption of HP1β chromatin binding during neurocognitive development. As HP1β forms homodimers and heterodimers, mutant HP1β likely sequesters wild-type HP1β and other HP1 proteins, exerting dominant-negative effects.