A Mutation in TNNC1-encoded Cardiac Troponin C, TNNC1-A31S, Predisposes to Hypertrophic Cardiomyopathy and Ventricular Fibrillation

Abstract

Background: Cardiac troponin C mutations are rare causes of HCM. A novel mutation in TNNC1 gene was identified in a pediatric HCM patient. Results: Functional characterization demonstrated increased myofilament Ca 2ϩ affinity. Conclusion:The proband presented with ventricular fibrillation, aborted sudden cardiac death associated with myofilament dysregulation. Significance: The newly identified cardiac troponin C mutation predisposes to pathogenesis of a fatal arrhythmogenic subtype of HCM.

Allosteric Transmission Along a Loosely Structured Backbone Allows a Cardiac Troponin C Mutant to Function with only One Ca 2+ ion

“…In the case of A31S, the subject carrying this mutation is prone to develop ventricular fibrillation. Although little is known about the structure of A31S, the secondary structure content is the same as that observed for WT, and in reconstituted fibers, Ca 2ϩ affinities and force development are increased (5). The cTnC D145E mutation carries an extra methylene at the Zϩ position of the coordinate sphere at site IV.…”

“…Subsequent reports identified mutations encoding primarily for sarcomeric proteins (3). New mutations in TNNC1 (A8V, A31S, and D145E), the gene that codifies cardiac troponin C (cTnC), have been observed in patients with HCM (4,5).…”

“…cTnC comprises two globular domains with a pair of EF-hand motifs in each domain. The N-domain Ca 2ϩ affinity (ϳ10 5 M Ϫ1 ) is lower than that of the C-domain (ϳ10 7 M Ϫ1 ) (8). Moreover, the N-domain site I has lost a Ca 2ϩ -coordinating carboxylate moiety (9), so that myofilament contraction is triggered by the binding of a single Ca 2ϩ ion to site II.…”

Allosteric Transmission along a Loosely Structured Backbone Allows a Cardiac Troponin C Mutant to Function with Only One Ca2+ Ion

“…Subsequent reports identified mutations encoding primarily for sarcomeric proteins (3). New mutations in TNNC1 (A8V, A31S, and D145E), the gene that codifies cardiac troponin C (cTnC), have been observed in patients with HCM (4,5).…”

“…cTnC comprises two globular domains with a pair of EF-hand motifs in each domain. The N-domain Ca 2ϩ affinity (ϳ10 5 M Ϫ1 ) is lower than that of the C-domain (ϳ10 7 M Ϫ1 ) (8). Moreover, the N-domain site I has lost a Ca 2ϩ -coordinating carboxylate moiety (9), so that myofilament contraction is triggered by the binding of a single Ca 2ϩ ion to site II.…”