Dominant-negative variants in CBX1 cause a neurodevelopmental disorder

Yukiko Kuroda; Aiko Iwata-Otsubo; Kerith-Rae Dias; Suzanna E.L. Temple; Koji Nagao; Lachlan De Hayr; Ying Zhu; Shin-Ya Isobe; Gohei Nishibuchi; Sarah K. Fiordaliso; Yuki Fujita; Alyssa L. Rippert; Samuel W. Baker; Marco L. Leung; Daniel C. Koboldt; Adele Harman; Beth A. Keena; Izumi Kazama; Gopinath Musuwadi Subramanian; Kandamurugu Manickam; Betsy Schmalz; Maeson Latsko; Elaine H. Zackai; Matt Edwards; Carey-Anne Evans; Matthew C. Dulik; Michael F. Buckley; Toshihide Yamashita; W. Timothy O'Brien; Robert J. Harvey; Chikashi Obuse; Tony Roscioli; Kosuke Izumi

doi:10.1016/j.gim.2023.100861

Back

Dominant-negative variants in CBX1 cause a neurodevelopmental disorder

Journal article

Peer reviewed

Dominant-negative variants in CBX1 cause a neurodevelopmental disorder

Yukiko Kuroda, Aiko Iwata-Otsubo, Kerith-Rae Dias, Suzanna E.L. Temple, Koji Nagao, Lachlan De Hayr, Ying Zhu, Shin-Ya Isobe, Gohei Nishibuchi, Sarah K. Fiordaliso, …

Genetics in Medicine, Vol.25(7), pp.1-14

2023

DOI: https://doi.org/10.1016/j.gim.2023.100861

PMID: 37087635

Appears in UniSC Diversity and Inclusion Research Collection

Files and links (1)

url

https://doi.org/10.1016/j.gim.2023.100861View

Published Version

Abstract

chromatin

Developmental disabilities

heterochromatin

histone

UniSC Diversity Area - Disability and Inclusion

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 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, 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.

Details

Title: Dominant-negative variants in CBX1 cause a neurodevelopmental disorder
Authors: Yukiko Kuroda (Author) - Children's Hospital of Philadelphia
Aiko Iwata-Otsubo (Author) - Children's Hospital of Philadelphia
Kerith-Rae Dias (Author) - Prince of Wales Hospital
Suzanna E.L. Temple (Author) - Prince of Wales Hospital
Koji Nagao (Author) - Osaka University
Lachlan De Hayr (Author) - University of the Sunshine Coast, Queensland, School of Health - Biomedicine
Ying Zhu (Author) - Prince of Wales Hospital
Shin-Ya Isobe (Author) - Osaka University
Gohei Nishibuchi (Author) - Osaka University
Sarah K. Fiordaliso (Author) - Children's Hospital of Philadelphia
Yuki Fujita (Author) - Osaka University
Alyssa L. Rippert (Author) - Children's Hospital of Philadelphia
Samuel W. Baker (Author) - Children's Hospital of Philadelphia
Marco L. Leung (Author) - Nationwide Children's Hospital
Daniel C. Koboldt (Author) - Nationwide Children's Hospital
Adele Harman (Author) - Children's Hospital of Philadelphia
Beth A. Keena (Author) - Children's Hospital of Philadelphia
Izumi Kazama (Author) - Children's Hospital of Philadelphia
Gopinath Musuwadi Subramanian (Author) - John Hunter Children's Hospital
Kandamurugu Manickam (Author) - The Ohio State University
Betsy Schmalz (Author) - Nationwide Children's Hospital
Maeson Latsko (Author) - Nationwide Children's Hospital
Elaine H. Zackai (Author) - Children's Hospital of Philadelphia
Matt Edwards (Author) - Hunter Genetics
Carey-Anne Evans (Author) - Prince of Wales Hospital
Matthew C. Dulik (Author) - Children's Hospital of Philadelphia
Michael F. Buckley (Author) - Prince of Wales Hospital
Toshihide Yamashita (Author) - Osaka University
W. Timothy O'Brien (Author) - University of Pennsylvania
Robert J. Harvey (Author) - University of the Sunshine Coast, Queensland, School of Health
Chikashi Obuse (Author) - Osaka University
Tony Roscioli (Author) - Prince of Wales Hospital
Kosuke Izumi (Corresponding Author) - Children's Hospital of Philadelphia
Publication details: Genetics in Medicine, Vol.25(7), pp.1-14
Publisher: Elsevier Inc.
Date published: 2023
DOI: 10.1016/j.gim.2023.100861
ISSN: 1530-0366
PMID: 37087635
Organisation Unit: School of Health - Biomedicine; University of the Sunshine Coast, Queensland; School of Health
Language: English
Record Identifier: 99719298902621
Output Type: Journal article

Metrics

13 Record Views

2 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Genetics & Heredity

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites