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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Multiple mutations in mouse Chd7 provide models for CHARGE syndrome
Erika A Bosman1, Andrew C Penn, John C Ambrose
1Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Abstract:
Mouse ENU mutagenesis programmes have yielded a series of independent mutations on proximal chromosome 4 leading to dominant head-bobbing and circling behaviour due to truncations of the lateral semicircular canal of the inner ear. Here, we report the identification of mutations in the Chd7 gene in nine of these mutant alleles including six nonsense and three splice site mutations. The human CHD7 gene is known to be involved in CHARGE syndrome, which also shows inner ear malformations and a variety of other features with varying penetrance and appears to be due to frequent de novo mutation. We found widespread expression of Chd7 in early development of the mouse in organs affected in CHARGE syndrome including eye, olfactory epithelium, inner ear and vascular system. Closer inspection of heterozygous mutant mice revealed a range of defects with reduced penetrance, such as cleft palate, choanal atresia, septal defects of the heart, haemorrhages, prenatal death, vulva and clitoral defects and keratoconjunctivitis sicca. Many of these defects mimic the features of CHARGE syndrome. There were no obvious features of the gene that might make it more mutable than other genes. We conclude that the large number of mouse mutants and human de novo mutations may be due to the combination of the Chd7 gene being a large target and the fact that many heterozygous carriers of the mutations are viable individuals with a readily detectable phenotype.
Insights
Mutations in the Chd7 gene cause inner ear defects and head-bobbing in mice, mimicking CHARGE syndrome features. This suggests Chd7
Area of Science:
- Genetics
- Developmental Biology
- Neuroscience
Background:
- ENU mutagenesis in mice identified mutations on chromosome 4 causing head-bobbing and circling.
- These behaviors are linked to truncations of the lateral semicircular canal in the inner ear.
Purpose of the Study:
- To identify the specific gene responsible for the observed head-bobbing and circling phenotypes in mouse mutants.
- To investigate the role of the identified gene in developmental defects and its relevance to human diseases like CHARGE syndrome.
Main Methods:
- Genetic analysis of nine independent mouse mutant alleles.
- Identification of mutations through sequencing of the candidate gene.
- Expression analysis of the gene during mouse embryonic development.
- Phenotypic characterization of heterozygous mutant mice.
Main Results:
- Nine of the mutant alleles were found to harbor mutations in the Chd7 gene (six nonsense, three splice site).
- Chd7 exhibits widespread expression in developing mouse organs, including the eye, olfactory epithelium, inner ear, and vascular system.
- Heterozygous Chd7 mutant mice displayed reduced penetrance of defects mimicking CHARGE syndrome, such as cleft palate, choanal atresia, and heart defects.
Conclusions:
- The Chd7 gene is implicated in the head-bobbing and circling phenotypes in mice, and its heterozygous mutations can cause a spectrum of developmental defects.
- These findings highlight the conserved role of Chd7 in mammalian development and provide a mouse model for studying CHARGE syndrome.
- The high frequency of mutations may be attributed to the large size of the Chd7 gene and the viability of heterozygous carriers with detectable phenotypes.
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