Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability

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 def...

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Bibliographic Details
Published in:Cell reports. Medicine 2022-02, Vol.3 (2), p.100501-100501, Article 100501
Main Authors: Teekakirikul, Polakit, Zhu, Wenjuan, Xu, Xinxiu, Young, Cullen B., Tan, Tuantuan, Smith, Amanda M., Wang, Chengdong, Peterson, Kevin A., Gabriel, George C., Ho, Sebastian, Sheng, Yi, Moreau de Bellaing, Anne, Sonnenberg, Daniel A., Lin, Jiuann-huey, Fotiou, Elisavet, Tenin, Gennadiy, Wang, Michael X., Wu, Yijen L., Feinstein, Timothy, Devine, William, Gou, Honglan, Bais, Abha S., Glennon, Benjamin J., Zahid, Maliha, Wong, Timothy C., Ahmad, Ferhaan, Rynkiewicz, Michael J., Lehman, William J., Keavney, Bernard, Alastalo, Tero-Pekka, Freckmann, Mary-Louise, Orwig, Kyle, Murray, Steve, Ware, Stephanie M., Zhao, Hui, Feingold, Brian, Lo, Cecilia W.
Format: Article
Language:English
Subjects:
Animals
ASD
atrial septal defect
CRISPR gene editing
embryonic lethality
genetic resiliency
Heart Septal Defects, Atrial - genetics
Humans
induced pluripotent stem cell
Mice
Microfilament Proteins
Mutation - genetics
Myofibrils
Pedigree
protective variant
Talin
TLN2
TPM1
Tropomyosin - genetics
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Summary: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. [Display omitted] •TPM1 mutation linked to atrial septal defect causes embryonic death with no heartbeat•TLN2 identified as protective variant suppressing the deleterious TPM1 mutation•CRISPR Tpm1/Tln2 double-KI mice show rescued heart beating and atrial septal defects•Functional annotation of variants of unknown significance with CRISPR founder analysis Pathogenic mutations known to cause severe disease can be found in healthy individuals, but the mechanism remains unknown. Teekakirikul et al. show suppression of embryonic lethality of a rare TPM1 mutation by suppressor variant in TLN2. Rescue of embryonic lethality also uncovers a role for TPM1 in atrial septal defect.
ISSN:2666-3791
2666-3791
DOI:10.1016/j.xcrm.2021.100501