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In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
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Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family.

Koichi Kato1,2, Holly M Isbell3, Véronique Fressart4

  • 1Sorbonne 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.).

Circulation. Arrhythmia and Electrophysiology
|February 28, 2022
PubMed
Summary
This summary is machine-generated.

A novel CALM3 variant, p.Asn138Lys, impairs calmodulin's calcium-binding and affects cardiac ion currents, explaining variable long QT syndrome severity. This finding provides insights into calmodulin-related cardiac arrhythmias.

Keywords:
calmodulinion channelslong QT syndromephenotypepotassium

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Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Biochemistry

Background:

  • Calmodulin (CaM) is crucial for signal transduction and ion channel regulation.
  • CaM variants are linked to severe cardiac arrhythmias like long QT syndrome (LQTS).
  • A novel CALM3 variant, p.Asn138Lys (N138K), was identified in a family with LQTS.

Purpose of the Study:

  • To elucidate the pathogenicity of the novel CALM3 p.N138K variant.
  • To compare the functional effects of p.N138K-CaM with the known p.D130G-CaM variant.
  • To understand the molecular mechanisms underlying variable LQTS phenotypes.

Main Methods:

  • Whole exome sequencing in an LQTS-affected family.
  • Measurement of CaM Ca2+ binding affinity using titrations.
  • Electrophysiological recordings (whole-cell patch-clamp) of ion currents (ICaL, IKs).
  • Assessment of Cav1.2 and Kv7.1 protein expression.

Main Results:

  • Identified 14 carriers of the p.N138K CALM3 variant within a 4-generation family.
  • p.N138K-CaM exhibited a 10-fold lower Ca2+ binding affinity.
  • Impaired ICaL inactivation and potentiated IKs currents were observed in cells expressing p.N138K-CaM.
  • The phenotype severity varied among affected family members.

Conclusions:

  • The p.N138K CALM3 variant reduces Ca2+ binding affinity and alters cardiac ion channel function (ICaL, IKs).
  • Variable LQTS phenotypes are likely due to milder ICaL impairment and IKs potentiation.
  • This study clarifies the pathogenicity of a novel CALM3 variant and its role in cardiac arrhythmias.