Document Type
Article
Publication Date
2-15-2022
Publication Title
Cell Rep Med
Keywords
JMG
JAX Source
Cell Rep Med 2022 Feb 15; 3(1):100501
Volume
3
Issue
2
First Page
100501
Last Page
100501
ISSN
2666-3791
PMID
35243414
DOI
https://doi.org/10.1016/j.xcrm.2021.100501
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 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.
Recommended Citation
Teekakirikul P,
Zhu W,
Xu X,
Young C,
Tan T,
Smith A,
Wang C,
Peterson K,
Gabriel G,
Ho S,
Sheng Y,
Moreau de Bellaing A,
Sonnenberg D,
Lin J,
Fotiou E,
Tenin G,
Wang M,
Wu Y,
Feinstein T,
Devine W,
Gou H,
Bais A,
Glennon B,
Zahid M,
Wong T,
Ahmad F,
Rynkiewicz M,
Lehman W,
Keavney B,
Alastalo T,
Freckmann M,
Orwig K,
Murray S,
Ware S,
Zhao H,
Feingold B,
Lo C.
Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability Cell Rep Med 2022 Feb 15; 3(1):100501
Comments
This is an open access article under the CC BY-NC-ND license.