PUBLICATION
Two distinct phenotypes in Snijders Blok-Campeau syndrome and characterization of the behavioral phenotype in a zebrafish model
- Authors
- Enomoto, Y., Shiromizu, T., Yasojima, S., Koiwa, J., Kuroda, Y., Ito, H., Yuge, M., Ohkawa, M., Shibata, R., Murakami, H., Naruto, T., Shiiya, S., Omotani, N., Nishimura, Y., Kurosawa, K.
- ID
- ZDB-PUB-250224-8
- Date
- 2025
- Source
- European journal of human genetics : EJHG : (Journal)
- Registered Authors
- Nishimura, Yuhei
- Keywords
- none
- MeSH Terms
-
- Disease Models, Animal
- Intellectual Disability*/genetics
- Intellectual Disability*/pathology
- Female
- Developmental Disabilities/genetics
- Developmental Disabilities/pathology
- Child, Preschool
- DNA Helicases*/genetics
- Humans
- Male
- Zebrafish Proteins/genetics
- Child
- Hypertelorism
- Animals
- Facies
- Phenotype*
- Behavior, Animal
- Zebrafish/genetics
- PubMed
- 39988727 Full text @ Eur. J. Hum. Genet.
Citation
Enomoto, Y., Shiromizu, T., Yasojima, S., Koiwa, J., Kuroda, Y., Ito, H., Yuge, M., Ohkawa, M., Shibata, R., Murakami, H., Naruto, T., Shiiya, S., Omotani, N., Nishimura, Y., Kurosawa, K. (2025) Two distinct phenotypes in Snijders Blok-Campeau syndrome and characterization of the behavioral phenotype in a zebrafish model. European journal of human genetics : EJHG. :.
Abstract
Chromatin remodeling is an important system controlling gene expression. CHD3, which is a causative gene of Snijders Blok-Campeau syndrome (SNIBCPS), is a member of the chromodomain helicase DNA-binding (CHD) family related to chromatin remodeling. SNIBCPS is characterized by developmental delay (DD), intellectual disability (ID), macrocephaly, and facial features including a prominent forehead and hypertelorism. Hypersociability/overfriendliness is a notable behavioral feature in patients. Here, we describe five SNIBCPS patients with CHD3 variants from four families, including a sibling pair caused by parental gonosomal mosaicism. We observed two distinct phenotypes in our patients in accordance with previous observations. Phenotype 1: macrocephaly, hypertelorism, overgrowth, DD, and ID; and Phenotype 2: microcephaly, growth retardation, DD, and ID. Phenotype 1 was consistent with the typical SNIBCPS phenotype, while Phenotype 2 was distinct. To understand further the features of the patients with SNIBCPS, we generated chd3-knockout (KO) zebrafish using CRISPR-Cas9 genome editing. No morphological changes were observed in chd3-KO zebrafish. However, behavioral tests showed that chd3-KO zebrafish had strong and sustained interest in others, and were less aggressive toward others, suggesting a recapitulation of the hypersociability/overfriendliness phenotype in patients with SNIBCPS. Metabolomic analysis using whole brains showed changes in metabolites processed by specific mitochondrial enzymes in chd3-KO zebrafish. The administration of metformin, which reportedly ameliorates mitochondrial dysfunction and behavioral abnormalities, attenuated the abnormal behavior of chd3-KO zebrafish. Our study helps delineate the phenotypes of patients with SNIBCPS, provides insights into a characteristic behavior of the disease, and suggests a potential treatment to improve the behavioral symptoms of patients.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping