Cellular mechanisms of mutations in Kv7.1: auditory functions in Jervell and Lange-Nielsen syndrome vs. Romanoâ€“Ward syndrome

Atefeh Mousavi Nik,Hyo Jeong Kim,Somayeh Gharaie

doi:10.3389/fncel.2015.00032

Atefeh Mousavi Nik, Hyo Jeong Kim + Show 1 more

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https://doi.org/10.3389/fncel.2015.00032

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Abstract

As a result of cell-specific functions of voltage-activated K+ channels, such as Kv7.1, mutations in this channel produce profound cardiac and auditory defects. At the same time, the massive diversity of K+ channels allows for compensatory substitution of mutant channels by other functional channels of their type to minimize defective phenotypes. Kv7.1 represents a clear example of such functional dichotomy. While several point mutations in the channel result in a cardio-auditory syndrome called Jervell and Lange-Nielsen syndrome (JLNS), about 100-fold mutations result in long QT syndrome (LQTS) denoted as Romano–Ward syndrome (RWS), which has an intact auditory phenotype. To determine whether the cellular mechanisms for the diverse phenotypic outcome of Kv7.1 mutations, are dependent on the tissue-specific function of the channel and/or specialized functions of the channel, we made series of point mutations in hKv7.1 ascribed to JLNS and RWS. For JLNS mutations, all except W248F yielded non-functional channels when expressed alone. Although W248F at the end of the S4 domain yielded a functional current, it underwent marked inactivation at positive voltages, rendering the channel non-functional. We demonstrate that by definition, none of the JLNS mutants operated in a dominant negative (DN) fashion. Instead, the JLNS mutants have impaired membrane trafficking, trapped in the endoplasmic reticulum (ER) and Cis-Golgi. The RWS mutants exhibited varied functional phenotypes. However, they can be summed up as exhibiting DN effects. Phenotypic differences between JLNS and RWS may stem from tissue-specific functional requirements of cardiac vs. inner ear non-sensory cells.

Highlights

Potassium (K+) channels perform diverse functions in cells, ranging from regulation of the membrane potential of excitable cells, controlling cell volume, cell division, migration and apoptotic cell death (DeCoursey et al, 1984; Bortner et al, 1997; Wei et al, 2004), as well as K+ outflow in specialized compartments in the body, e.g., the kidney and inner ear (Giebisch, 2001; Nin et al., 2008, 2012)
In this study, we investigated the biophysical and cellular effects of seemingly similar mutations in KCNQ1 which result in phenotypic differences between Jervell and Lange-Nielsen syndrome (JLNS) and Romano–Ward syndrome (RWS)
We selected mutations which were identified in JLNS vs. RWS patients, but in most cases their cellular mechanisms were unknown

Summary

Introduction

Potassium (K+) channels perform diverse functions in cells, ranging from regulation of the membrane potential of excitable cells, controlling cell volume, cell division, migration and apoptotic cell death (DeCoursey et al, 1984; Bortner et al, 1997; Wei et al, 2004), as well as K+ outflow in specialized compartments in the body, e.g., the kidney and inner ear (Giebisch, 2001; Nin et al., 2008, 2012). After the human genome was delineated, it was reassuring to identify K+ channel genes as the most varied ion channel in the body (Gutman et al, 2005; Wulff et al, 2009). The cell-specific functions of K+ channels are such that mutations in these channels often result in a plethora of pathological conditions. This is because in K+ channelopathy, other K+ channels can hardly compensate for their loss or gain of functions. Because K+ channels operate in multicomponent systems, it is extremely difficult to identify their subunit-specific functions. In order to define their subtypespecific functions, studies in heterologous expression systems are used routinely

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