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 and
neurobehavioral and cytological analyses of neuronal cells obtained from newly generated
Cbx1 mutant mouse lines.
Results
In 3 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 HP1β,
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, whereas 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. Because HP1β forms homodimers and heterodimers, mutant
HP1β likely sequesters wild-type HP1β and other HP1 proteins, exerting dominant-negative
effects.
Keywords
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Article info
Publication history
Published online: April 20, 2023
Accepted:
April 16,
2023
Received in revised form:
April 16,
2023
Received:
January 17,
2023
Publication stage
In Press Corrected ProofFootnotes
Yukiko Kuroda and Aiko Iwata-Otsubo contributed equally to this work.
Chikashi Obuse, Tony Roscioli, and Kosuke Izumi contributed equally to this work.
Identification
Copyright
© 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
