Dominant-negative variants in CBX1 cause a neurodevelopmental disorder

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Heterochromatin protein 1β (HP1β), encoded by CBX1, plays a crucial role in chromatin regulation.
• Disruptions in neurodevelopmental pathways can lead to complex syndromic disorders.

Purpose of the Study:

• To identify genetic variants in CBX1 associated with a novel syndromic neurodevelopmental disorder.
• To investigate the functional impact of these variants on HP1β function and neurodevelopment.

Main Methods:

• Patient identification through GeneMatcher and physician referrals.
• In vitro cellular assays and neurobehavioral/cytological analyses in Cbx1 mutant mouse models.
• Chromatin immunoprecipitation and interactome analysis to assess HP1β binding and interactions.

Main Results:

• Heterozygous de novo variants in the CBX1 chromodomain were identified in three unrelated individuals with developmental delay, hypotonia, and autistic features.
• Cbx1 mutant mice exhibited synaptic delay or myelination deficits, indicated by increased latency-to-peak response.
• Mutant HP1β showed reduced binding to heterochromatin, though most interacting proteins remained unchanged.

Conclusions:

• CBX1 variants disrupt HP1β chromatin binding, contributing to developmental disabilities.
• Mutant HP1β likely exerts dominant-negative effects by sequestering wild-type HP1β and other HP1 proteins.
• This study establishes CBX1 as a significant gene in neurocognitive development.