Genetic Mosaicism in Calmodulinopathy-Reference-Cited by-同舟云学术

Genetic Mosaicism in Calmodulinopathy

Published:2019-09 Issue:9 Volume:12 Page:
ISSN:2574-8300
Container-title:Circulation: Genomic and Precision Medicine
language:en
Short-container-title:Circ: Genomic and Precision Medicine

Author:

Wren Lisa M.¹,Jiménez-Jáimez Juan²,Al-Ghamdi Saleh³,Al-Aama Jumana Y.⁴⁵,Bdeir Amnah⁵,Al-Hassnan Zuhair N.⁶,Kuan Jyn L.⁷,Foo Roger Y.⁷,Potet Franck¹,Johnson Christopher N.⁸,Aziz Miriam C.⁹,Carvill Gemma L.⁹,Kaski Juan-Pablo¹⁰,Crotti Lia¹¹¹²¹³,Perin Francesca¹⁴,Monserrat Lorenzo¹³,Burridge Paul W.¹,Schwartz Peter J.¹²,Chazin Walter J.⁸,Bhuiyan Zahurul A.¹⁵,George Alfred L.¹

Affiliation:

1. From the Department of Pharmacology (L.M.W., F.P., P.W.B., A.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL

2. Cardiology Department (J.J.-J.), Virgen de las Nieves Hospital, Granada, Spain

3. Cardiac Sciences Department, Section of Pediatric Cardiology, King Abdulaziz Cardiac Center, Ministry of National Guard Health Affairs, Riyadh (S.A.-G.)

4. Department of Genetic Medicine, Faculty of Medicine (J.Y.A.-A.), King Abdulaziz University, Jeddah

5. Princess Al Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders (J.Y.A.-A., A.B.), King Abdulaziz University, Jeddah

6. The Cardiovascular Genetics Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia (Z.N.A.-H.)

7. Department of Cardiology, National University Heart Center and Cardiovascular Research Institute, National University of Singapore (J.L.K., R.Y.F.)

8. Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN (C.N.J., W.J.C.)

9. Department of Neurology (M.C.A., G.L.C.), Northwestern University Feinberg School of Medicine, Chicago, IL

10. Institute of Cardiovascular Science, University College London, United Kingdom (J.-P.K.)

11. Department of Medicine and Surgery, University of Milano-Bicocca (L.C.)

12. IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., P.J.S.)

13. Cardiology Department, Health in Code SL, A Coruña, Spain (L.M.)

14. Pediatric Cardiology Division (F.P.), Virgen de las Nieves Hospital, Granada, Spain

15. Unité de Recherche Cardiogénétique, Service de Médecine Génétique, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland (Z.A.B.).

Abstract

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 Ca 2+ 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 Ca 2+ -dependent inactivation of L-type Ca 2+ channels and prolonged action potential duration. Conclusions: We report 2 families with somatic mosaicism associated with arrhythmogenic calmodulinopathy, and demonstrate dysregulation of L-type Ca 2+ 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

General Medicine

Reference35 articles.

1. Calmodulinopathy: A genetic trilogy

2. Mutations in Calmodulin Cause Ventricular Tachycardia and Sudden Cardiac Death

3. Calmodulin Mutations Associated With Recurrent Cardiac Arrest in Infants

4. 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

5. A Mutation in CALM1 Encoding Calmodulin in Familial Idiopathic Ventricular Fibrillation in Childhood and Adolescence

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