Calmodulin mutations associated with recurrent cardiac arrest in infants

Lia Crotti, Christopher N. Johnson, Elisabeth Graf, Gaetano M. De Ferrari, Bettina F. Cuneo, Marc Ovadia, John Papagiannis, Michael D. Feldkamp, Subodh G. Rathi, Jennifer D. Kunic, Matteo Pedrazzini, Thomas Wieland, Peter Lichtner, Britt Maria Beckmann, Travis Clark, Christian Shaffer, D. Woodrow Benson, Stefan Kääb, Thomas Meitinger, Tim M. StromWalter J. Chazin, Peter J. Schwartz, Alfred L. George

Research output: Contribution to journalArticle

180 Citations (Scopus)

Abstract

Background-: Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause. Methods and Results-: We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2, 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity. Conclusions-: Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.

Original languageEnglish
Pages (from-to)1009-1017
Number of pages9
JournalCirculation
Volume127
Issue number9
DOIs
Publication statusPublished - Mar 5 2013

Fingerprint

Calmodulin
Heart Arrest
Mutation
Exome
Calcium
Ion Channels
Genes
Long QT Syndrome
Calcium Signaling
Sudden Death
Cardiac Arrhythmias
Epilepsy
Carrier Proteins
Parents
Ions

Keywords

  • arrhythmia
  • calcium signaling
  • death, sudden, cardiac
  • exome

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Calmodulin mutations associated with recurrent cardiac arrest in infants. / Crotti, Lia; Johnson, Christopher N.; Graf, Elisabeth; De Ferrari, Gaetano M.; Cuneo, Bettina F.; Ovadia, Marc; Papagiannis, John; Feldkamp, Michael D.; Rathi, Subodh G.; Kunic, Jennifer D.; Pedrazzini, Matteo; Wieland, Thomas; Lichtner, Peter; Beckmann, Britt Maria; Clark, Travis; Shaffer, Christian; Benson, D. Woodrow; Kääb, Stefan; Meitinger, Thomas; Strom, Tim M.; Chazin, Walter J.; Schwartz, Peter J.; George, Alfred L.

In: Circulation, Vol. 127, No. 9, 05.03.2013, p. 1009-1017.

Research output: Contribution to journalArticle

Crotti, L, Johnson, CN, Graf, E, De Ferrari, GM, Cuneo, BF, Ovadia, M, Papagiannis, J, Feldkamp, MD, Rathi, SG, Kunic, JD, Pedrazzini, M, Wieland, T, Lichtner, P, Beckmann, BM, Clark, T, Shaffer, C, Benson, DW, Kääb, S, Meitinger, T, Strom, TM, Chazin, WJ, Schwartz, PJ & George, AL 2013, 'Calmodulin mutations associated with recurrent cardiac arrest in infants', Circulation, vol. 127, no. 9, pp. 1009-1017. https://doi.org/10.1161/CIRCULATIONAHA.112.001216
Crotti, Lia ; Johnson, Christopher N. ; Graf, Elisabeth ; De Ferrari, Gaetano M. ; Cuneo, Bettina F. ; Ovadia, Marc ; Papagiannis, John ; Feldkamp, Michael D. ; Rathi, Subodh G. ; Kunic, Jennifer D. ; Pedrazzini, Matteo ; Wieland, Thomas ; Lichtner, Peter ; Beckmann, Britt Maria ; Clark, Travis ; Shaffer, Christian ; Benson, D. Woodrow ; Kääb, Stefan ; Meitinger, Thomas ; Strom, Tim M. ; Chazin, Walter J. ; Schwartz, Peter J. ; George, Alfred L. / Calmodulin mutations associated with recurrent cardiac arrest in infants. In: Circulation. 2013 ; Vol. 127, No. 9. pp. 1009-1017.
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AU - Crotti, Lia

AU - Johnson, Christopher N.

AU - Graf, Elisabeth

AU - De Ferrari, Gaetano M.

AU - Cuneo, Bettina F.

AU - Ovadia, Marc

AU - Papagiannis, John

AU - Feldkamp, Michael D.

AU - Rathi, Subodh G.

AU - Kunic, Jennifer D.

AU - Pedrazzini, Matteo

AU - Wieland, Thomas

AU - Lichtner, Peter

AU - Beckmann, Britt Maria

AU - Clark, Travis

AU - Shaffer, Christian

AU - Benson, D. Woodrow

AU - Kääb, Stefan

AU - Meitinger, Thomas

AU - Strom, Tim M.

AU - Chazin, Walter J.

AU - Schwartz, Peter J.

AU - George, Alfred L.

PY - 2013/3/5

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N2 - Background-: Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause. Methods and Results-: We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2, 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity. Conclusions-: Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.

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KW - exome

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