Journal Article

Multiple mutations in mouse <i>Chd7</i> provide models for CHARGE syndrome

Erika A. Bosman, Andrew C. Penn, John C. Ambrose, Ross Kettleborough, Derek L. Stemple and Karen P. Steel

in Human Molecular Genetics

Volume 14, issue 22, pages 3463-3476
Published in print November 2005 | ISSN: 0964-6906
Published online October 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi375

Show Summary Details

Preview

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.

Journal Article.  10878 words.  Illustrated.

Subjects: Genetics and Genomics

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.