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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.

SUBMITTER: Teekakirikul P

PROVIDER: S-EPMC8861813 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Teekakirikul Polakit P Zhu Wenjuan W Xu Xinxiu X Young Cullen B CB Tan Tuantuan T Smith Amanda M AM Wang Chengdong C Peterson Kevin A KA Gabriel George C GC Ho Sebastian S Sheng Yi Y Moreau de Bellaing Anne A Sonnenberg Daniel A DA Lin Jiuann-Huey JH Fotiou Elisavet E Tenin Gennadiy G Wang Michael X MX Wu Yijen L YL Feinstein Timothy T Devine William W Gou Honglan H Bais Abha S AS Glennon Benjamin J BJ Zahid Maliha M Wong Timothy C TC Ahmad Ferhaan F Rynkiewicz Michael J MJ Lehman William J WJ Keavney Bernard B Alastalo Tero-Pekka TP Freckmann Mary-Louise ML Orwig Kyle K Murray Steve S Ware Stephanie M SM Zhao Hui H Feingold Brian B Lo Cecilia W CW

Cell reports. Medicine 20220215 2

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 pluripoten ...[more]

PMID: 35243414

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Project description:Background Delayed brain development, brain injury, and neurodevelopmental disabilities are commonly observed in infants operated for complex congenital heart defect. Our previous findings of poorer neurodevelopmental outcomes in individuals operated for simple congenital heart defects calls for further etiological clarification. Hence, we examined the microstructural tissue composition in cerebral cortex and subcortical structures in comparison to healthy controls and whether differences were associated with neurodevelopmental outcomes. Methods and Results Adults (n=62) who underwent surgical closure of an atrial septal defect (n=33) or a ventricular septal defect (n=29) in childhood and a group of healthy, matched controls (n=38) were enrolled. Brain diffusional kurtosis imaging and neuropsychological assessment were performed. Cortical and subcortical tissue microstructure were assessed using mean kurtosis tensor and mean diffusivity and compared between groups and tested for associations with neuropsychological outcomes. Alterations in microstructural tissue composition were found in the parietal, temporal, and occipital lobes in the congenital heart defects, with distinct mean kurtosis tensor cluster-specific changes in the right visual cortex (pericalcarine gyrus, P=0.002; occipital part of fusiform and lingual gyri, P=0.019). Altered microstructural tissue composition in the subcortical structures was uncovered in atrial septal defects but not in ventricular septal defects. Associations were found between altered cerebral microstructure and social recognition and executive function. Conclusions Children operated for simple congenital heart defects demonstrated altered microstructural tissue composition in the cerebral cortex and subcortical structures during adulthood when compared with healthy peers. Alterations in cerebral microstructural tissue composition were associated with poorer neuropsychological performance. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871881.

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

Publications

Genetic resiliency associated with dominant lethal <i>TPM1</i> mutation causing atrial septal defect with high heritability.

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

Publications

Genetic resiliency associated with dominant lethal &lt;i&gt;TPM1&lt;/i&gt; mutation causing atrial septal defect with high heritability.

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OmicsDI is part of the ELIXIR infrastructure

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Genetic resiliency associated with dominant lethal <i>TPM1</i> mutation causing atrial septal defect with high heritability.