Chromatin remodeling by the CHD7 protein is impaired by mutations that cause human developmental disorders.

Mutations in the CHD7 gene cause human developmental disorders including CHARGE syndrome. Genetic studies in model organisms have further established CHD7 as a central regulator of vertebrate development. Functional analysis of the CHD7 protein has been hampered by its large size. We used a dual-tag system to purify intact recombinant CHD7 protein and found that it is an ATP-dependent nucleosome remodeling factor. Biochemical analyses indicate that CHD7 has characteristics distinct from SWI/SNF- and ISWI-type remodelers. Further investigations show that CHD7 patient mutations have consequences that range from subtle to complete inactivation of remodeling activity, and that mutations leading to protein truncations upstream of amino acid 1899 of CHD7 are likely to cause a hypomorphic phenotype for remodeling. We propose that nucleosome remodeling is a key function for CHD7 during developmental processes and provide a molecular basis for predicting the impact of disease mutations on that function.