Unraveling monogenic channelopathies and their implications for complex polygenic disease

Abstract

Ion channels are a large family of >400 related proteins representing >1% of our genetic endowment; however, ion-channel diseases reflect a relatively new category of inborn error. They were first recognized in 1989, with the discovery of cystic fibrosis transmembrane conductance regulator, and rapidly advanced as positional and functional studies converged in the dissection of components of the action potential of excitable tissues. Although it remains true that diseases of excitable tissue still most clearly illustrate this family of disease, ion-channel disorders now cover the gamut of medical disciplines, causing significant pathology in virtually every organ system, producing a surprising range of often unanticipated symptoms, and providing valuable targets for pharmacological intervention. Many of the features shared among the monogenic ion-channel diseases provide a general framework for formulating a foundation for considering their intrinsically promising role in polygenic disease. Since an increasingly important approach to the identification of genes underlying polygenic disease is to identify "functional candidates" within a critical region and to test their disease association, it becomes increasingly important to appreciate how these ion-channel mechanisms can be implicated in pathophysiology.

Figure 1

Time correlation of EKG waves, ventricular myocyte action potential, and the individual participating ion currents. a, EKG trace, with each component wave labeled above, and QT interval, from the start of the Q wave to the end of the T wave, indicated with brackets. LQT syndrome prolongs this interval. b, Ventricular cardiac myocyte action potential correlated in time with the EKG above. The plateau phase of prolonged depolarization is indicated. By convention, depolarization is an upward deflection from the baseline. c, Ion currents underlying myocyte action potential, correlated in time with the EKG and action potential. Individual traces are shown for a pure sodium, potassium, and calcium current, the sum of which produces the action potential. Sodium and calcium channels produce depolarizing currents, reflected as an upward deflection. Potassium channels produce a hyperpolarizing current, reflected as a downward deflection.

Figure 2

Ventricular cardiac myocyte action potential, showing the contribution of individual ion channels and gene products. The name of the current is placed adjacent to the time at which it predominates in the action potential. Upward arrows indicate a depolarizing current; downward arrows indicate a hyperpolarizing current. The name of the genes contributing the channel subunits are placed adjacent to the current name. Each gene named has dominant alleles that produce the RW LQT syndrome. The two genes forming the I_Ks channel also have recessive alleles producing the JLN LQT syndrome.