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http://purl.uniprot.org/citations/31454269http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/31454269http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/31454269http://www.w3.org/2000/01/rdf-schema#comment"

Background

CaM (calmodulin) mutations are associated with congenital arrhythmia susceptibility (calmodulinopathy) and are most often de novo. In this report, we sought to broaden the genotype-phenotype spectrum of calmodulinopathies with 2 novel calmodulin mutations and to investigate mosaicism in 2 affected families.

Methods

CaM mutations were identified in 4 independent cases by DNA sequencing. Biochemical and electrophysiological studies were performed to determine functional consequences of each mutation.

Results

Genetic studies identified 2 novel CaM variants (CALM3-E141K in 2 cases; CALM1-E141V) and one previously reported CaM pathogenic variant (CALM3-D130G) among 4 probands with shared clinical features of prolonged QTc interval (range 505-725 ms) and documented ventricular arrhythmia. A fatal outcome occurred for 2 of the cases. The parents of all probands were asymptomatic with normal QTc duration. However, 2 of the families had multiple affected offspring or multiple occurrences of intrauterine fetal demise. The mother from the family with recurrent intrauterine fetal demise exhibited the CALM3-E141K mutant allele in 25% of next-generation sequencing reads indicating somatic mosaicism, whereas CALM3-D130G was present in 6% of captured molecules of the paternal DNA sample, also indicating mosaicism. Two novel mutations (E141K and E141V) impaired Ca2+ binding affinity to the C-domain of CaM. Human-induced pluripotent stem cell-derived cardiomyocytes overexpressing mutant or wild-type CaM showed that both mutants impaired Ca2+-dependent inactivation of L-type Ca2+ channels and prolonged action potential duration.

Conclusions

We report 2 families with somatic mosaicism associated with arrhythmogenic calmodulinopathy, and demonstrate dysregulation of L-type Ca2+ channels by 2 novel CaM mutations affecting the same residue. Parental mosaicism should be suspected in families with unexplained fetal arrhythmia or fetal demise combined with a documented CaM mutation."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.org/dc/terms/identifier"doi:10.1161/circgen.119.002581"xsd:string
http://purl.uniprot.org/citations/31454269http://purl.org/dc/terms/identifier"doi:10.1161/circgen.119.002581"xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Al-Aama J.Y."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Al-Aama J.Y."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Al-Hassnan Z.N."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Al-Hassnan Z.N."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"George A.L. Jr."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"George A.L. Jr."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Chazin W.J."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Chazin W.J."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Potet F."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Potet F."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Schwartz P.J."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Schwartz P.J."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Carvill G.L."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Carvill G.L."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Crotti L."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Crotti L."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Al-Ghamdi S."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Al-Ghamdi S."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Aziz M.C."xsd:string
http://purl.uniprot.org/citations/31454269http://purl.uniprot.org/core/author"Aziz M.C."xsd:string
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