Novel Calmodulin Mutations Associated With Congenital Arrhythmia Susceptibility

Abstract

Background Genetic predisposition to life-threatening cardiac arrhythmias such as in congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations. Methods and Results We employed conventional and next-generation sequencing approaches including exome analysis in genotype-negative LQTS probands. We identified five novel de novo missense mutations in CALM2 in three subjects with LQTS (p.N98S, p.N98I, p.D134H) and two subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1–9 years. Three of five probands had cardiac arrest and one of these subjects did not survive. Although all probands had LQTS, two subjects also exhibited electrocardiographic features consistent with CPVT. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of five probands responded to β-blocker therapy whereas one subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within calcium binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced calcium binding affinity. Conclusions CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.

Catecholaminergic Polymorphic Ventricular Tachycardia

“…39 Apart from CPVT, mutations in CALM1 have also been associated with congenital long-QT syndrome and idiopathic ventricular fibrillation. 40, 41 Mutations in CALM2 have been reported in 2 separate papers 40, 42 and have been associated with congenital long-QT syndrome and with overlapping features between congenital long-QT syndrome and CPVT. 40, 42 Finally, mutations in the genes ANK2, encoding ankyrin-B, and KCNJ2, encoding the potassium inwardly rectifying channel Kir2.1, are generally associated with the congenital long-QT syndrome types 4 and 7, respectively, but may phenocopy CPVT.…”

Whole-Exome Molecular Autopsy After Exertion-Related Sudden Unexplained Death in the Young

“…Mutations in all 3 calmodulin genes have been implicated previously in LQTS or CPVT. [15][16][17][18][19] The CALM2-N98S mutation was identified in a 2-year-old boy who died while dancing. This CALM2-N98S was seen previously as a sporadic mutation in a 12-year-old Japanese boy with syncope and QT prolongation.…”

“…This CALM2-N98S was seen previously as a sporadic mutation in a 12-year-old Japanese boy with syncope and QT prolongation. 18 The CALM2-F90L mutation was identified in a 5-year-old boy who died while playing. Although CALM2-F90L is novel, a CALM1-F90L mutation has been described previously.…”

Conserved properties of individual Ca 2+ -binding sites in calmodulin

“…In humans it binds to more than 300 targets (1)(2)(3). Humans have three genes that encode identical CaM proteins, but mutations in just one of the three copies can cause disease (4)(5)(6)(7)(8), as can altered gene expression (9). Although CaM has been extensively studied, many details about its function are still poorly understood.…”