Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes.

Détails

ID Serval
serval:BIB_4D0474E4A1C5
Type
Article: article d'un périodique ou d'un magazine.
Sous-type
Etude de cas (case report): rapporte une observation et la commente brièvement.
Collection
Publications
Titre
Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes.
Périodique
Heart rhythm
Auteur(s)
Pipilas D.C., Johnson C.N., Webster G., Schlaepfer J., Fellmann F., Sekarski N., Wren L.M., Ogorodnik K.V., Chazin D.M., Chazin W.J., Crotti L., Bhuiyan Z.A., George A.L.
ISSN
1556-3871 (Electronic)
ISSN-L
1547-5271
Statut éditorial
Publié
Date de publication
10/2016
Peer-reviewed
Oui
Volume
13
Numéro
10
Pages
2012-2019
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS).
The purpose of this study was to determine the clinical, genetic, and functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias.
The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations.
A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca(2+) affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell-derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca(2+)-dependent inactivation of voltage-gated Ca(2+) current. Neither mutant affected voltage-dependent inactivation.
Our findings implicate impaired Ca(2+)-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.

Pubmed
Création de la notice
07/07/2016 14:09
Dernière modification de la notice
20/08/2019 15:01
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