Congenital heart disease in mice deficient for the DiGeorge syndrome region

The heterozygous chromosome deletion within the band 22q11 (del22q11) is an important cause of congenital cardiovascular defects(1), It is the genetic basis of DiGeorge syndrome and causes the most common deletion syndrome in humans(2). Because the deleted region is largely conserved in the mouse, w e were able to engineer a chromosome deletion (Df1) spanning a segment of t he murine region homologous to the human deleted region. Here we describe h eterozygously deleted (Df1/+) mice with cardiovascular abnormalities of the same type as those associated with del22q11; we have traced the embryologi cal origin of these abnormalities to defective development of the fourth ph aryngeal arch arteries. Genetic complementation of the deletion using a chr omosome duplicated for the Df1 DNA segment corrects the heart defects, indi cating that they are caused by reduced dosage of genes located within Df1. The Df1/+ mouse model reveals the pathogenic basis of the most clinically s evere aspect of DiGeorge syndrome and uncovers a new mechanism leading to a ortic arch abnormalities. These mutants represent a mouse model of a human deletion syndrome generated by chromosome engineering.