Por favor, use este identificador para citar o enlazar a este item:
http://hdl.handle.net/10261/201600
COMPARTIR / EXPORTAR:
SHARE CORE BASE | |
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE | |
Título: | In vitro analyses of suspected arrhythmogenic thin filament variants as a cause of sudden cardiac death in infants |
Autor: | Shafaattalab, Sanam; Li, Alison Yueh; Lin, Eric; Stevens, Charles M.; Dewar, Laura J.; Lynn, Francis C.; Sanatani, Shubhayan; Laksman, Zachary; Morin, Ryan D.; Petegem, Filip van; Hove-Madsen, Leif CSIC ORCID; Tieleman, D. Peter; Davis, Jonathan P.; Tibbits, Glen F. | Palabras clave: | Cardiac troponin Thin filament HiPSC-CM Sudden cardiac death Arrhythmias |
Fecha de publicación: | 2-abr-2019 | Editor: | National Academy of Sciences (U.S.) | Citación: | Proceedings of the National Academy of Sciences of the USA 116: 6969-6974 (2019) | Resumen: | Sudden unexpected death of an infant (SUDI) is a devastating occurrence for families. To investigate the genetic pathogenesis of SUDI, we sequenced >70 genes from 191 autopsy-negative SUDI victims. Ten infants sharing a previously unknown variant in troponin I (TnI) were identified. The mutation (TNNI1 R37C/) is in the fetal/neonatal paralog of TnI, a gene thought to be expressed in the heart up to the first 24 months of life. Using phylogenetic analysis and molecular dynamics simulations, it was determined that arginine at residue 37 in TNNI1 may play a critical functional role, suggesting that the variant may be pathogenic. We investigated the biophysical properties of the TNNI1 R37C mutation in human reconstituted thin filaments (RTFs) using fluorometry. RTFs reconstituted with the mutant R37C TnI exhibited reduced Ca-binding sensitivity due to an increased Ca off-rate constant. Furthermore, we generated TNNI1 R37C/ mutants in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) using CRISPR-Cas9. In monolayers of hiPSC-CMs, we simultaneously monitored voltage and Ca transients through optical mapping and compared them to their isogenic controls. We observed normal intrinsic beating patterns under control conditions in TNNI1 R37C/− at stimulation frequencies of 55 beats/min (bpm), but these cells showed no restitution with increased stimulation frequency to 65 bpm and exhibited alternans at >75 bpm. The WT hiPSC-CMs did not exhibit any sign of arrhythmogenicity even at stimulation frequencies of 120 bpm. The approach used in this study provides critical physiological and mechanistic bases to investigate sarcomeric mutations in the pathogenesis of SUDI. | Versión del editor: | http://dx.doi.org/10.1073/pnas.1819023116 | URI: | http://hdl.handle.net/10261/201600 | DOI: | 10.1073/pnas.1819023116 | Identificadores: | doi: 10.1073/pnas.1819023116 e-issn: 1091-6490 issn: 0027-8424 |
Aparece en las colecciones: | (IIBB) Artículos |
Ficheros en este ítem:
Fichero | Descripción | Tamaño | Formato | |
---|---|---|---|---|
accesoRestringido.pdf | 15,38 kB | Adobe PDF | Visualizar/Abrir |
CORE Recommender
PubMed Central
Citations
7
checked on 22-abr-2024
SCOPUSTM
Citations
12
checked on 23-abr-2024
WEB OF SCIENCETM
Citations
10
checked on 26-feb-2024
Page view(s)
189
checked on 24-abr-2024
Download(s)
22
checked on 24-abr-2024
Google ScholarTM
Check
Altmetric
Altmetric
Artículos relacionados:
NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.