A Mouse Model with Complete Penetrance for Atrioventricular Septal Defect/Complete AV Canal

Abstract

AbstractComplete Atrioventricular Septal Defect/complete AV canal (AVSD/ cAVC) occurs via defective formation of the Dorsal Mesenchymal Protrusion (DMP) which grows from the interior dorsal wall of the fetal heart. The DMP is derived from cells of the second heart field (SHF). AVSD occurs in about 1/10,000 births in the general population, but is 2000 times more prevalent in individuals with Down syndrome (DS). The low penetrance of AVSD in the general population remains a fundamental challenge to investigation of the genetic and developmental basis for this condition. Analysis of the etiology of this condition in mouse models is limited by the fact that the developmental events producing the DMP begin around embryonic day 9 (E9) but AVSD cannot be diagnosed until E14, and no model has been described previously in which AVSD occurs in 100% of embryos. We describe a trisomic mouse DS model with conditional mutations in the SHH pathway that produces AVSD with 100% penetrance. This new mouse model can serve as an important tool to understand the mechanisms underlying AVSD pathogenesis.