Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family

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.