CUL1 variants cause severe neurodevelopmental disorders: Insights from human genetics and a zebrafish model of microcephaly

Microcephaly is a neurodevelopmental anomaly characterized by reduced head circumference and impaired brain growth, often accompanied by intellectual disability (ID), developmental delays, and seizures. While numerous genes have been implicated in microcephaly, the role of the SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complex, particularly its core component CUL1, remains poorly understood. In this study, we identified heterozygous de novo and inherited variants in the CUL1 gene in four unrelated families with severe microcephaly, ID, and developmental delays. To investigate the functional consequences of CUL1 loss of function, we developed a zebrafish model with knockdown of cul1a&b, which exhibited significant reductions in central nervous system size and behavioral defects, mirroring the clinical phenotypes observed in patients. These findings establish CUL1 as a novel gene associated with severe neurodevelopmental disorders (NDDs) and highlight its critical role in brain development. Our study provides genotype-phenotype correlations for CUL1 in NDDs, expanding the genetic spectrum of disorders linked to the SCF complex and underscoring its importance in neurodevelopment.

Authors

Institutions

Publication Details

Journal
Human Genetics and Genomics Advances
Published
2025-11-05
DOI
https://doi.org/10.1016/j.xhgg.2025.100542
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

CUL1 variants cause severe neurodevelopmental disorders: Insights from human genetics and a zebrafish model of microcephaly

Sainan Hu, Hao‐Ling Xu, Jing Duan, Yiqiao Chen et al.
Human Genetics and Genomics Advances
Genomics and Rare Diseases
article

CUL1 variants cause severe neurodevelopmental disorders: Insights from human genetics and a zebrafish model of microcephaly

Sainan Hu, Hao‐Ling Xu, Jing Duan, Yiqiao Chen, Jinping Su, Qin-yong Ye, Jacques L. Michaud, Mei He, Jinfang Hu, Peng Yin, Li Chen, Dan Wang, Zhen Liu, Pan Hu, Jianxiang Liao, Shengnan Wu, Fadi F. Hamdan, Berge A. Minassian
article en

Abstract

Microcephaly is a neurodevelopmental anomaly characterized by reduced head circumference and impaired brain growth, often accompanied by intellectual disability (ID), developmental delays, and seizures. While numerous genes have been implicated in microcephaly, the role of the SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complex, particularly its core component CUL1, remains poorly understood. In this study, we identified heterozygous de novo and inherited variants in the CUL1 gene in four unrelated families with severe microcephaly, ID, and developmental delays. To investigate the functional consequences of CUL1 loss of function, we developed a zebrafish model with knockdown of cul1a&b, which exhibited significant reductions in central nervous system size and behavioral defects, mirroring the clinical phenotypes observed in patients. These findings establish CUL1 as a novel gene associated with severe neurodevelopmental disorders (NDDs) and highlight its critical role in brain development. Our study provides genotype-phenotype correlations for CUL1 in NDDs, expanding the genetic spectrum of disorders linked to the SCF complex and underscoring its importance in neurodevelopment.

Human Genetics and Genomics AdvancesVol. 7(1)
Fujian Medical University (CN), Sun Yat-sen University (CN), Centre Hospitalier Universitaire Sainte-Justine (CA), Sun Yat-sen Memorial Hospital (CN), Shenzhen Children's Hospital (CN), Shanghai Children's Hospital (CN), Union Hospital (CN), Hunan Provincial Maternal and Child Health Hospital (CN), The University of Texas Southwestern Medical Center (US)
Openalex Percentile: Top 65%
Genomics and Rare Diseases
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.