Genetic resiliency associated with dominant lethal TPM1 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 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.

• Authors: Polakit Teekakirikul, Wenjuan Zhu, Xinxiu Xu, Cullen B Young, Tuantuan Tan, Amanda M Smith, Chengdong Wang, Kevin A Peterson, George C Gabriel, Sebastian Ho, Yi Sheng, Anne Moreau de Bellaing, Daniel A Sonnenberg, Jiuann-Huey Lin, Elisavet Fotiou, Gennadiy Tenin, Michael X Wang, Yijen L Wu, Timothy Feinstein, William Devine, Honglan Gou, Abha S Bais, Benjamin J Glennon, Maliha Zahid, Timothy C Wong, Ferhaan Ahmad, Michael J Rynkiewicz, William J Lehman, Bernard Keavney, Tero-Pekka Alastalo, Mary-Louise Freckmann, Kyle Orwig, Steve Murray, Stephanie M Ware, Hui Zhao, Brian Feingold, Cecilia W Lo
• Journal: Cell reports. Medicine (Cell Rep Med) Vol. 3 Issue 2 Pg. 100501 (02 15 2022) ISSN: 2666-3791 [Electronic] United States
• PMID: 35243414 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Author(s).

Chemical References

• Microfilament Proteins
• TLN2 protein, mouse
• TPM1 protein, human
• Talin
• Tpm1 protein, mouse
• Tropomyosin

Topics

• Animals
• Heart Septal Defects, Atrial (genetics)
• Humans
• Mice
• Microfilament Proteins
• Mutation (genetics)
• Myofibrils
• Pedigree
• Talin
• Tropomyosin (genetics)