Session S45.3

Identification of the Phenotypes of Multi-Mechanism Mutations Attributed to Long QT Syndrome

C Wang, CD Nugent*, P Beyerlein, A Krause, W Dubitzky

University of Ulster
Coleraine, Northern Ireland, UK

The severity of clinical phenotypes of the mutated genes attributed to LQTS may be accounted for by their cellular phenotypes. Nevertheless, some uncertainties can arise when genetic mutations render cardiac ion channel proteins to dysfunction through multiple molecular mechanisms, and result in some confusion about their functional consequences. In this study we use computational modeling to identity the phenotypes of such a kind of mutation residing in the KCNH2 gene and demonstrate how the integrative study can help to improve the prediction as well as the interpretation of QT abnormality caused by the defective gene.
Conformational kinetic models of cardiac ion channels encoded by mutated KCNH2 were established to characterize the functional properties of channel proteins at the sub-cellular level. An optimization algorithm searching for the transition probability functions of the models has been derived by use of the matrix exponentials and perturbation analysis. The directional derivatives of the matrix exponentials were obtained through operating on the augmented matrix defined as a block triangular form. The closed-form method was presented using Frobenius inner product. The functional effect of genetic defects was investigated by integrating conformational models into a cellular model under physiological conditions.
Compared to the control condition, the altered inactivation due to the 2616delC mutation was prone to shortening the action potential duration, hence indicative for a short QT syndrome. However, the decreased densities (up to 28%) mimicking the pathological condition due to trafficking deficiency prolonged action potential duration. In the membrane potentials from -20 mV to +20 mV, the critical range for the plateau phase of cardiac repolarization, the functional consequence of allosterically coupled modulations is a prolonged action potential repolarization process.
Our results suggest that the severe clinical manifestation of the 2616delC mutation is LQTS induced by the predominant dysfunction from traffic deficiency. The closed-form algorithms are easy to implement and to establish the computer models simulating pathological conditions caused by genetic mutations, and therefore are helpful for improving the quality of pre-symptomatic diagnosis.

(Abstract Control Number: 123)