a-pipeline-to-characterize-structural-heart-defects-in-the-fetal-mouse

A Pipeline to Characterize Structural Heart Defects in the Fetal Mouse

Congenital heart diseases (CHDs) are major causes of infant death in the United States. In the 1980s and earlier, most patients with moderate or severe ...

University of Pittsburgh

Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in , a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with  mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in , another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the  and  variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of  in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective  variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.

Benjamin J. Glennon

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JoVE Journal Publications

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