Electrophysiological Recording of a Gain-of-Function Polycystin-2 Channel with a Two-Electrode Voltage Clamp
Jinghua Hu, Yong Yu in Polycystic Kidney Disease, 2019
Genetic studies have revealed that the linker region between S4 and S5 (S4-S5 linker) and the first half of S5 helix is a hot spot for GOF mutations of many TRP channels.23 Mutations at this region have been linked to over activity-induced channelopathies in human beings. For example, N855S in TRPA1 causes familial episodic pain syndrome,24 G573S in TRPV3 causes Olmsted syndrome,25 multiple mutations in this region of TRPV4 cause various skeletal dysplasias and motor/sensory neuropathies,26,27 and multiple mutations of TRPML1 have been found to be the underlying cause of mucolipidosis type IV.28 Some other GOF mutations of TRP channels have been generated by doing mutagenesis screens, which also fall into this region.29 These GOF mutations paved the way for scientists to study the function and regulation of these channels, especially for those that are difficult to be activated extrinsically or intrinsically.
Death from natural causes
Jason Payne-James, Richard Jones in Simpson's Forensic Medicine, 2019
The channelopathies are a group of disorders representing a proportion of sudden deaths, presumed to be of cardiac origin. SCD following ventricular tachyarrhythmias constitutes an important clinical cause of mortality; 4 per cent of cases may involve ion channel-mediated cellular excitation in structurally normal hearts. Changes in these mechanisms may disturb action potential conduction, depolarisation/repolarisation gradients, or Ca2+ homeostasis with potential arrhythmogenic consequences. Defects in genes encoding myocyte contractile units have been characterised and these affect the function of sodium, potassium and calcium channels. Patients may present with symptoms of palpitations or haemodynamic compromise, including dizziness, seizure or syncope, particularly following exertion. In all inherited cardiac death syndromes, first-degree relatives should be referred to a cardiologist and should undergo testing appropriate for the condition.
The pathophysiology of primary headache
Stephen D. Silberstein, Richard B. Upton, Peter J. Goadsby in Headache in Clinical Practice, 2018
Migraine is a feature of some of the mitochondrial disorders, such as MELAS (mitochondrial encephalopathy lactic acidosis stroke-like episodes). This association, and the very many observations of clinicians over time, drew attention to the possible genetic basis for migraine. The first genetic locus for a migrainous disease was found on chromosome 19pl3 for familial hemiplegic migraine (FHM).1 This was the beginning of an extensive effort to unravel the fundamental defect(s) that leads to migraine. The gene for FHM has been mapped to chromosome 19pl3 in some, but not all, families (Figure 5.1). This region may also be involved in more common forms of migraine.2–3 The defect in FHM has been found to be owing, in five families, to four different missense mutations in a P/Q Ca2+ channel alpha-l-subunit gene CACNAIA covering 300 kb with 47 exons.4 This is the same gene associated with episodic ataxia with cerebellar vermal atrophy.5 P/Q-type neuronal Ca2+ channels mediate 5-hydroxytryptamine (5-HT) release. Dysfunction of these channels may impair 5-HT release and predispose patients to migraine attacks or impair their self-aborting mechanism. Magnesium deficiency occurs in the cortex of migraineurs,6 and magnesium interacts with Ca2+ channels. Ca2+ channels are important in spreading depression, which may initiate the migraine aura. Impaired function may predispose to more frequent and severe attacks. This suggests that migraine may be part of the spectrum of channelopathies.
Ion channels as therapeutic antibody targets
Published in mAbs, 2019
Catherine J. Hutchings, Paul Colussi, Theodore G. Clark
The human genome encodes at least 400 ion channel family members (~1.5%1), representing the second largest class of membrane proteins for drug discovery after G protein-coupled receptors (GPCRs) (Figure1(a)).2-5 Roughly 18% of small molecule drugs listed in the ChEMBL database are targeted towards ion channels,5 with global sales estimated to be $12 billion.6 Although it is well validated that ion channels are at the core of many diseases, approved drugs are available for only a small percentage of this protein class (approx. 8%) despite focused drug discovery efforts over the past 30 years.7 Ion channels function by transporting ions across cell membranes and play important roles in a broad range of physiological and pathophysiological processes. Mutations of single ion channel proteins have been demonstrated to be the cause of genetic diseases, collectively known as channelopathies.8 For example, mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) lead to cystic fibrosis, whereas various pain syndromes, including congenital indifference to pain and paroxysmal extreme pain disorder, are associated with either loss or gain of function mutations, respectively, in the SCN9A gene encoding the voltage-gated sodium channel Nav1.7. Along with direct effects on the functionality of ion channel subunits or the proteins that regulate them, channelopathies can also result from autoimmune responses to channel proteins.9
Improving genetic diagnostics of skeletal muscle channelopathies
Published in Expert Review of Molecular Diagnostics, 2020
Vinojini Vivekanandam, Roope Männikkö, Emma Matthews, Michael G. Hanna
Mutations in genes that are not ion channels or that are not expressed in skeletal muscle can present with symptoms associated with skeletal muscle channelopathies. SLC2A1 is implicated in Glucose Transporter Deficiency Syndrome [24]. While this is not a skeletal muscle channelopathy, the episodic symptoms predominantly affect the lower limbs and are often triggered by movement or exercise, which can cause diagnostic confusion with periodic paralysis. Glucose Transport Deficiency syndromes are highly treatable and should not be missed. CACNA1A encodes calcium channel Cav2.1 with neuronal expression. It is implicated in Familial Hemiplegic Migraine and Episodic Ataxia type 2 [25]. These conditions can also have overlapping symptoms or cause diagnostic confusion with presentations of skeletal muscle channelopathies including paresis, and share common triggers. Expansion from a four gene to a seven-gene panel has improved diagnostic rates of previously undiagnosed rare causes of channelopathies and allows parallel diagnosis of channelopathy mimics.
From next-generation sequencing to targeted treatment of non-acquired epilepsies
Published in Expert Review of Molecular Diagnostics, 2019
Rikke S. Møller, Trine B. Hammer, Guido Rubboli, Johannes R. Lemke, Katrine M. Johannesen
Next-generation sequencing (NGS) has become part of routine diagnostic work-up.NGS (gene panel, exome sequencing or genome sequencing) should be considered as the first-tier diagnostic test in patients with early-onset epilepsy.The number of epilepsy genes has raised to more than 700 genes.The diagnostic yield of NGS in developmental and/or epileptic encephalopathies is approximately 25–30%.Channelopathies are among the most common causes of developmental and/or epileptic encephalopathies.A genetic cause may be found in up to 20% of the patients with familial focal epilepsies.
Related Knowledge Centers
- Electrochemical Gradient
- Heredity
- Mutation
- Myotonia Congenita
- Protein
- Skeletal Muscle
- Ion Channel
- Gene
- Long Qt Syndrome
- Periodic Paralysis