| First Author | Teekakirikul P | Year | 2022 |
| Journal | Cell Rep Med | Volume | 3 |
| Issue | 2 | Pages | 100501 |
| PubMed ID | 35243414 | Mgi Jnum | J:320916 |
| Mgi Id | MGI:6883556 | Doi | 10.1016/j.xcrm.2021.100501 |
| Citation | Teekakirikul P, et al. (2022) Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability. Cell Rep Med 3 |
| abstractText | Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe dis-ease 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 ï¬ve-generation pedigree. Mice with Tpm1 mutation exhibit early embryonic lethality with disrupted myoï¬bril as-sembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myoï¬lament defect, indicating disease suppression. A variant in TLN2, another myoï¬lament actin-binding protein, is identiï¬ed 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 ï¬ndings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation. |
