Genetic resiliency associated with dominant lethal <i>TPM1</i> mutation causing atrial septal defect with high heritability.

ABSTRACT: 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 TPM1, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with Tpm1 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 TLN2, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the TLN2 and TPM1 varian

SUBMITTER: Teekakirikul P 

PROVIDER: S-EPMC8861813 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature