PUBLICATION
Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation
- Authors
- Ahlberg, G., Refsgaard, L., Lundegaard, P.R., Andreasen, L., Ranthe, M.F., Linscheid, N., Nielsen, J.B., Melbye, M., Haunsø, S., Sajadieh, A., Camp, L., Olesen, S.P., Rasmussen, S., Lundby, A., Ellinor, P.T., Holst, A.G., Svendsen, J.H., Olesen, M.S.
- ID
- ZDB-PUB-181020-7
- Date
- 2018
- Source
- Nature communications 9: 4316 (Journal)
- Registered Authors
- Ellinor, Patrick, Lundegaard, Pia Rengtved
- Keywords
- none
- MeSH Terms
-
- Atrial Fibrillation/genetics*
- Atrial Fibrillation/pathology
- Genetic Variation
- Fibrosis
- Male
- Female
- Zebrafish
- Aged
- Humans
- Adult
- Cohort Studies
- Sarcomeres/metabolism
- Sarcomeres/ultrastructure
- Myocardium/metabolism
- Myocardium/ultrastructure
- Case-Control Studies
- Young Adult
- Connectin/genetics*
- Connectin/metabolism
- Animals
- PubMed
- 30333491 Full text @ Nat. Commun.
Citation
Ahlberg, G., Refsgaard, L., Lundegaard, P.R., Andreasen, L., Ranthe, M.F., Linscheid, N., Nielsen, J.B., Melbye, M., Haunsø, S., Sajadieh, A., Camp, L., Olesen, S.P., Rasmussen, S., Lundby, A., Ellinor, P.T., Holst, A.G., Svendsen, J.H., Olesen, M.S. (2018) Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation. Nature communications. 9:4316.
Abstract
A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10-6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10-6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping