New CHARGE Syndrome Mouse Models Reveal the Contribution of the Enzymatic Activity of CHD7 in Pathogenesis

Genetic variants of CHD7, encoding a chromatin remodeler, lead to CHARGE syndrome with congenital deficits in multiple organs. One crucial unsolved question is the causal mechanisms of most protein-altering variants of CHD7. One hypothesis is that these variants impair the enzymatic activity of CHD7, that is ATPase and nucleosome remodeling activities. Herein, we compared the phenotype of two new mouse models for CHARGE syndrome in parallel, with the Dppa3-cre/Chd7^f/+ line carrying a Chd7 truncation variant and the Chd7^S824F/+ line carrying an enzymatic-deficient missense variant. While the Dppa3-cre/Chd7^f/+ line displayed typical disease-relevant phenotypes of CHARGE syndrome as other reported lines, some of these phenotypes, such as body growth and circling behavior, were surprisingly mild in the ATPase-deficient Chd7^S824F/+ mouse line. Thus, our results demonstrated the different contribution of the enzymatic activity of CHD7 in growth and organogenesis.