Key result
Protective TLN2 variant suppresses embryonic lethality of a dominant TPM1 mutation, allowing survival with ASD.
Why the study?
Large-scale human genomic data revealed unexplained mutations causing severe disease in healthy individuals, including a dominant lethal TPM1 mutation associated with atrial septal defect.
A protective TLN2 variant can suppress the embryonic lethality of a dominant lethal TPM1 mutation, leading to the development of atrial septal defects instead of embryonic death.
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 variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of TPM1 in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective TLN2 variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.
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Teekakirikul et al. (2022) studied Atrial septal defect (n=8). TPM1 mutation and TLN2 variant was evaluated. A protective TLN2 variant suppressed the embryonic lethality of a dominant lethal TPM1 mutation, allowing survival with a large atrial septal defect.
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