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Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G. 2016

Nicole J Boczek, and Nieves Gomez-Hurtado, and Dan Ye, and Melissa L Calvert, and David J Tester, and Dmytro Kryshtal, and Hyun Seok Hwang, and Christopher N Johnson, and Walter J Chazin, and Christina G Loporcaro, and Maully Shah, and Andrew L Papez, and Yung R Lau, and Ronald Kanter, and Bjorn C Knollmann, and Michael J Ackerman
Department Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN.

BACKGROUND Calmodulin (CaM) is encoded by 3 genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to Ca(2+) and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants. RESULTS Thirty-eight genetically elusive LQTS cases underwent whole-exome sequencing to identify CaM variants. Nonsynonymous CaM variants were over-represented significantly in this heretofore LQTS cohort (13.2%) compared with exome aggregation consortium (0.04%; P<0.0001). When the clinical sequelae of these 5 CaM-positive cases were compared with the 33 CaM-negative cases, CaM-positive cases had a more severe phenotype with an average age of onset of 10 months, an average corrected QT interval of 676 ms, and a high prevalence of cardiac arrest. Functional characterization of 1 novel variant, E141G-CaM, revealed an 11-fold reduction in Ca(2+)-binding affinity and a functionally dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release. CONCLUSIONS Overall, 13% of our genetically elusive LQTS cohort harbored nonsynonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history.

UI MeSH Term Description Entries
D008133 Long QT Syndrome A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME. Electrocardiogram QT Prolonged
D008297 Male Males
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D002147 Calmodulin A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. Calcium-Dependent Activator Protein,Calcium-Dependent Regulator,Bovine Activator Protein,Cyclic AMP-Phosphodiesterase Activator,Phosphodiesterase Activating Factor,Phosphodiesterase Activator Protein,Phosphodiesterase Protein Activator,Regulator, Calcium-Dependent,AMP-Phosphodiesterase Activator, Cyclic,Activating Factor, Phosphodiesterase,Activator Protein, Bovine,Activator Protein, Calcium-Dependent,Activator Protein, Phosphodiesterase,Activator, Cyclic AMP-Phosphodiesterase,Activator, Phosphodiesterase Protein,Calcium Dependent Activator Protein,Calcium Dependent Regulator,Cyclic AMP Phosphodiesterase Activator,Factor, Phosphodiesterase Activating,Protein Activator, Phosphodiesterase,Protein, Bovine Activator,Protein, Calcium-Dependent Activator,Protein, Phosphodiesterase Activator,Regulator, Calcium Dependent
D003710 Demography Statistical interpretation and description of a population with reference to distribution, composition, or structure. Demographer,Demographic,Demographic and Health Survey,Population Distribution,Accounting, Demographic,Analyses, Demographic,Analyses, Multiregional,Analysis, Period,Brass Technic,Brass Technique,Demographers,Demographic Accounting,Demographic Analysis,Demographic Factor,Demographic Factors,Demographic Impact,Demographic Impacts,Demographic Survey,Demographic Surveys,Demographic and Health Surveys,Demographics,Demography, Historical,Demography, Prehistoric,Factor, Demographic,Factors, Demographic,Family Reconstitution,Historical Demography,Impact, Demographic,Impacts, Demographic,Multiregional Analysis,Period Analysis,Population Spatial Distribution,Prehistoric Demography,Reverse Survival Method,Stable Population Method,Survey, Demographic,Surveys, Demographic,Analyses, Period,Analysis, Demographic,Analysis, Multiregional,Demographic Analyses,Demographies, Historical,Demographies, Prehistoric,Distribution, Population,Distribution, Population Spatial,Distributions, Population,Distributions, Population Spatial,Family Reconstitutions,Historical Demographies,Method, Reverse Survival,Method, Stable Population,Methods, Reverse Survival,Methods, Stable Population,Multiregional Analyses,Period Analyses,Population Distributions,Population Methods, Stable,Population Spatial Distributions,Prehistoric Demographies,Reconstitution, Family,Reconstitutions, Family,Reverse Survival Methods,Spatial Distribution, Population,Spatial Distributions, Population,Stable Population Methods,Technic, Brass,Technique, Brass
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015995 Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from INCIDENCE, which refers to the number of new cases in the population at a given time. Period Prevalence,Point Prevalence,Period Prevalences,Point Prevalences,Prevalence, Period,Prevalence, Point,Prevalences

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