Journal article
Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability
Cell reports. Medicine, Vol.3(2), pp.100501-100501
02/15/2022
DOI: 10.1016/j.xcrm.2021.100501
PMCID: PMC8861813
PMID: 35243414
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.
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•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.
Details
- Title: Subtitle
- Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability
- Creators
- Polakit Teekakirikul - University of PittsburghWenjuan Zhu - Chinese University of Hong KongXinxiu Xu - University of PittsburghCullen B. Young - University of PittsburghTuantuan Tan - University of PittsburghAmanda M. Smith - Indiana UniversityChengdong Wang - Chinese University of Hong KongKevin A. Peterson - Jackson LaboratoryGeorge C. Gabriel - University of PittsburghSebastian Ho - University of PittsburghYi Sheng - Magee-Womens Research InstituteAnne Moreau de Bellaing - Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADaniel A. Sonnenberg - University of PittsburghJiuann-huey Lin - University of PittsburghElisavet Fotiou - University of ManchesterGennadiy Tenin - University of ManchesterMichael X. Wang - University of PittsburghYijen L. Wu - University of PittsburghTimothy Feinstein - University of PittsburghWilliam Devine - University of PittsburghHonglan Gou - BGI GroupAbha S. Bais - University of PittsburghBenjamin J. Glennon - University of PittsburghMaliha Zahid - University of PittsburghTimothy C. Wong - University of PittsburghFerhaan Ahmad - University of IowaMichael J. Rynkiewicz - Boston UniversityWilliam J. Lehman - Boston UniversityBernard Keavney - University of ManchesterTero-Pekka Alastalo - Blueprint MedicinesMary-Louise Freckmann - Royal North Shore HospitalKyle Orwig - Magee-Womens Research InstituteSteve Murray - Jackson LaboratoryStephanie M. Ware - Indiana UniversityHui Zhao - Chinese University of Hong KongBrian Feingold - Children's Hospital of PittsburghCecilia W. Lo - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Cell reports. Medicine, Vol.3(2), pp.100501-100501
- DOI
- 10.1016/j.xcrm.2021.100501
- PMID
- 35243414
- PMCID
- PMC8861813
- NLM abbreviation
- Cell Rep Med
- ISSN
- 2666-3791
- eISSN
- 2666-3791
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 02/15/2022
- Academic Unit
- Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984297506702771
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