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@ -196,12 +196,12 @@ Although the genetic nature of ion channel mutations as well as their effects on
%\par\null
\section*{Introduction (750 Words Maximum - Currently 704)}
\section*{Introduction (750 Words Maximum - Currently 708)}
%\textit{The Introduction should briefly indicate the objectives of the study and provide enough background information to clarify why the study was undertaken and what hypotheses were tested.}
The properties and combinations of voltage-gated ion channels are vital in determining neuronal excitability \citep{bernard_channelopathies_2008, carbone_ion_2020, rutecki_neuronal_1992, pospischil_minimal_2008}. However, ion channel function can be disturbed, for instance through genetic alterations, resulting in altered neuronal firing behavior \citep{carbone_ion_2020}.
\textit{In recent years, next generation sequencing has led to an increasing number of clinically relevant ion channel mutations and has provided the basis for pathophysiological studies of genetic epilepsies, pain disorders, dyskinesias, intellectual disabilities, myotonias, and periodic paralyses \citep{bernard_channelopathies_2008, carbone_ion_2020}.}
\textcolor{red}{In recent years, next generation sequencing has led to an increase in discoveries of clinically relevant ion channel mutations and has provided the basis for pathophysiological studies of genetic epilepsies, pain disorders, dyskinesias, intellectual disabilities, myotonias, and periodic paralyses \citep{bernard_channelopathies_2008, carbone_ion_2020}.}
%\textit{In recent years, next generation sequencing has led to an increasing number of clinically relevant ion channel mutations and has provided the basis for pathophysiological studies of genetic epilepsies, pain disorders, dyskinesias, intellectual disabilities, myotonias, and periodic paralyses \citep{bernard_channelopathies_2008, carbone_ion_2020}.}
In recent years, next generation sequencing has led to an increase in the discovery of clinically relevant ion channel mutations and has provided the basis for pathophysiological studies of genetic epilepsies, pain disorders, dyskinesias, intellectual disabilities, myotonias, and periodic paralyses \citep{bernard_channelopathies_2008, carbone_ion_2020}.
Ongoing efforts of many research groups have contributed to the current understanding of underlying disease mechanism in channelopathies, however a complex pathophysiological landscape has emerged for many channelopathies and is likely a reason for limited therapeutic success with standard care.
Ion channel variants are frequently classified in heterologous expression systems as either a loss of function (LOF) or a gain of function (GOF) in the respective ionic current \citep{Musto2020, Kullmann2002, Waxman2011, Kim2021}. This LOF/GOF classification is often directly used to predict the effects on neuronal firing \citep{Niday2018, Wei2017, Wolff2017,Masnada2017}, which in turn is important for understanding the pathophysiology of these disorders and for identification of potential therapeutic targets \citep{Orsini2018, Yang2018, Colasante2020, Yu2006}. Experimentally, the effects of channelopathies on neuronal firing are assessed using primary neuronal cultures \citep{Scalmani2006, Smith2018, Liu2019} or \textit{in vitro} recordings from slices of transgenic mouse lines \citep{Mantegazza2019, Xie2010,Lory2020, Habib2015, Hedrich14874} but are restricted to limited number of neuronal types. Different neuron types differ in their composition of ionic currents \citep{yao2021taxonomy, Cadwell2016, BICCN2021, Scala2021} and therefore likely respond differently to changes in the properties of a single ionic current. Expression level of an affected gene \citep{Layer2021} and relative amplitudes of ionic currents \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012} indeed dramatically influence the firing behavior and dynamics of neurons. Mutations in different sodium channel genes have been experimentally shown to affect firing in a cell-type specific manner based on differences in expression levels of the affected gene \citep{Layer2021}, but also on other cell-type specific mechanisms \citep{Hedrich14874, makinson_scn1a_2016}.