Journal article
Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family
Circulation. Arrhythmia and electrophysiology, Vol.15(3), e010572
02/28/2022
DOI: 10.1161/CIRCEP.121.010572
PMID: 35225649
Abstract
CaM (calmodulin), encoded by 3 separate genes (
,
, and
), is a multifunctional Ca
-binding protein involved in many signal transduction events including ion channel regulation. CaM variants may present with early-onset long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia, or sudden cardiac death. Most reported variants occurred de novo. We identified a novel
variant, p.Asn138Lys (N138K), in a 4-generation family segregating with LQTS. The aim of this study was to elucidate its pathogenicity and to compare it with that of p.D130G-CaM-a variant associated with a severe LQTS phenotype.
We performed whole exome sequencing for a large, 4-generation family affected by LQTS. To assess the effect of the detected
variant, the intrinsic Ca
-binding affinity was measured by stoichiometric Ca
titrations and equilibrium titrations. L-type Ca
and slow delayed rectifier potassium currents (I
and I
) were recorded by whole-cell patch-clamp. Cav1.2 and Kv7.1 membrane expression were determined by optical fluorescence assays.
We identified 14 p.N138K-CaM carriers in a family where 2 sudden deaths occurred in children. Several members were only mildly affected compared with CaM-LQTS patients to date described in literature. The intrinsic Ca
-binding affinity of the CaM C-terminal domain was 10-fold lower for p.N138K-CaM compared with WT-CaM. I
inactivation was slowed in cells expressing p.N138K-CaM but less than in p.D130G-CaM cells. Unexpectedly, a larger I
current density was observed in cells expressing p.N138K-CaM, but not for p.D130G-CaM, compared with WT-CaM.
The p.N138K
variant impairs Ca
-binding affinity of CaM and I
inactivation but potentiates I
. The variably expressed phenotype of this variant compared with previously published de novo LQTS-CaM variants is likely explained by a milder impairment of I
inactivation combined with I
augmentation.
Details
- Title: Subtitle
- Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family
- Creators
- Koichi Kato - Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan (K.K.)Holly M Isbell - Department of Biochemistry, Carver College of Medicine, University of Iowa (H.M.I., M.A.S.)Véronique Fressart - AP-HP, Pitié-Salpêtrière Hospital, Functional Unit of Cardiogenetics and Myogenetics, Paris, France (V.F.)Isabelle Denjoy - AP-HP, Bichat Hospital, HUPNVS, Referring Center for Rare Cardiac Diseases, Sorbonne University, Paris, France (I.D.)Amal Debbiche - Sorbonne Université, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, UMRS-1166, Paris, France (K.K., V.F., I.D., A.D., A.C., P.G.)Hideki Itoh - Division of Patient Safety, Hiroshima University Hospital, Japan (H.I.)Jacques Poinsot - Tours University, France (J.P.)Alfred L George Jr - Northwestern University Feinberg School of Medicine, Chicago, IL (A.L.G.)Alain Coulombe - Sorbonne Université, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, UMRS-1166, Paris, France (K.K., V.F., I.D., A.D., A.C., P.G.)Madeline A Shea - Department of Biochemistry, Carver College of Medicine, University of Iowa (H.M.I., M.A.S.)Pascale Guicheney - Sorbonne Université, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, UMRS-1166, Paris, France (K.K., V.F., I.D., A.D., A.C., P.G.)
- Resource Type
- Journal article
- Publication Details
- Circulation. Arrhythmia and electrophysiology, Vol.15(3), e010572
- DOI
- 10.1161/CIRCEP.121.010572
- PMID
- 35225649
- NLM abbreviation
- Circ Arrhythm Electrophysiol
- eISSN
- 1941-3084
- Language
- English
- Date published
- 02/28/2022
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology
- Record Identifier
- 9984222739602771
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