A5054603978- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Genetic Neurodegenerative Diseases
- Cardiomyopathy and Myosin Studies
- Neuroscience and Neural Engineering
- Neuroscience and Neuropharmacology Research
- Pancreatic function and diabetes
- Cardiac Ischemia and Reperfusion
- Muscle Physiology and Disorders
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Myasthenia Gravis and Thymoma
- Genomics and Rare Diseases
- Neuroscience of respiration and sleep
- Amyotrophic Lateral Sclerosis Research
- Receptor Mechanisms and Signaling
- Neurogenetic and Muscular Disorders Research
- Ion Transport and Channel Regulation
- Neurological disorders and treatments
- Nicotinic Acetylcholine Receptors Study
- Glycogen Storage Diseases and Myoclonus
- Heart Failure Treatment and Management
- Signaling Pathways in Disease
- Thyroid and Parathyroid Surgery
- Ion Channels and Receptors
- RNA Research and Splicing
National Hospital for Neurology and Neurosurgery
2016-2025
University College London
2015-2024
MRC Prion Unit
2014-2019
Tampere University
2017-2019
University of California, Los Angeles
2019
Vaasa Central Hospital
2017-2019
University of Helsinki
2017
University of Oxford
2009-2016
Centre National de la Recherche Scientifique
2015
Université Laval
2015
Abstract AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca 2+ -impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients intellectual disability (ID) neurodevelopmental...
See Cannon (doi: 10.1093/brain/awv400 ) for a scientific commentary on this article. Congenital myopathies are clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia weakness, specific pathological features biopsy. The phenotype ranges from foetal akinesia resulting in utero neonatal mortality, to milder that not life-limiting. Over the past decade, more than 20 new myopathy genes have been identified. Most encode proteins...
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels are important for rhythmic activity in the brain and heart. In this study, using ionic gating current measurements, we show that cloned spHCN undergo a hysteresis their voltage dependence during normal gating. For example, both charge versus curve, Q(V), conductance G(V), shifted by about +60 mV when measured from hyperpolarized holding potential compared with depolarized potential. addition, kinetics of tail activation...
Gain-of-function mutations in Kir6.2 (KCNJ11), the pore-forming subunit of adenosine triphosphate (ATP)-sensitive potassium (KATP) channel, cause neonatal diabetes. Many patients also suffer from hypotonia (weak and flaccid muscles) balance problems. The diabetes arises suppressed insulin secretion by overactive KATP channels pancreatic beta-cells, but source motor phenotype is unknown. By using mice carrying a human mutation (Val59-->Met59) targeted to either muscle or nerve, we show that...
The finding that patients with diabetes due to potassium channel mutations can transfer from insulin sulfonylureas has revolutionised the management of permanent neonatal diabetes. extent which in vitro characteristics mutation predict a successful is not known. Our aim was identify factors associated KCNJ11 (which encodes inwardly rectifying Kir6.2). We retrospectively analysed clinical data on 127 who attempted sulfonylureas. considered when completely discontinued whilst All unsuccessful...
BackgroundSudden infant death syndrome (SIDS) is the leading cause of post-neonatal in high-income countries. Central respiratory system dysfunction seems to contribute these deaths. Excitation that drives contraction skeletal muscles controlled by sodium channel NaV1.4, which encoded gene SCN4A. Variants NaV1.4 directly alter muscle excitability can myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found infants with life-threatening...
<h3>Objective:</h3> To determine the molecular basis of a complex phenotype congenital muscle weakness observed in an isolated but consanguineous patient. <h3>Methods:</h3> The proband was evaluated clinically and neurophysiologically over period 15 years. Genetic testing candidate genes performed. Functional characterization mutation done mammalian cell background using whole patch clamp technique. <h3>Results:</h3> had fatigable characteristic myasthenic syndrome with acute reversible...
Voltage-gated ion channels respond to changes in the transmembrane voltage by opening or closing their conducting pore. The positively charged fourth segment (S4) has been identified as main sensor, but mechanisms of coupling between sensor and gates are still unknown. Obtaining information about location exact motion S4 is an important step toward understanding these mechanisms. In previous studies we have shown that extracellular end located close 5 (S5). purpose present study estimate...
Hyperpolarization-activated, cyclic-nucleotide-gated (HCN) channels regulate pacemaker activity in the heart and brain. Previously, we showed that spHCN HCN1 undergo mode shifts their voltage dependences, shifting conductance versus curves by more than +50 mV when measured from a hyperpolarized potential compared to depolarized potential. In addition, kinetics of ionic currents changed parallel these shifts. studies reported here, tested whether slower cardiac HCN also display similar We...
The X-ray crystallographic structure of KvAP, a voltage-gated bacterial K channel, was recently published. However, the position and molecular movement voltage sensor, S4, are still controversial. For example, in structure, S4 is located far away (&gt;30 Å) from pore domain, whereas electrostatic experiments have suggested that close (&lt;8 to domain open channels. To test proposed location motion relative we induced disulphide bonds between pairs introduced cysteines: one domain....
Research Article12 June 2009Open Access Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism Kenju Shimomura Henry Wellcome Centre for Gene Function, Department Physiology, Anatomy Genetics, University Oxford, UK Search more papers by this author Sarah E. Flanagan Institute Biomedical Clinical Research, Peninsula Medical School, Exeter, Brittany Zadek Mark Lethby Lejla Zubcevic Christophe A. J. Girard Oliver Petz St. Vincenz Hospital Coesfeld,...
Hypokalaemic periodic paralysis is a rare genetic neuromuscular disease characterized by episodes of skeletal muscle associated with low serum potassium. Muscle fibre inexcitability during attacks due to an aberrant depolarizing leak current through mutant voltage sensing domains either the sarcolemmal voltage-gated calcium or sodium channel. We report child hypokalaemic and CNS involvement, including seizures, but without mutations in known genes. identified novel heterozygous de novo...
To identify the genetic and physiologic basis for recessive myasthenic congenital myopathy in 2 families, suggestive of a channelopathy involving sodium channel gene, SCN4A. A combination whole exome sequencing targeted mutation analysis, followed by voltage-clamp studies mutant channels expressed fibroblasts (HEK cells) Xenopus oocytes. Missense mutations same residue skeletal muscle channel, R1460 NaV1.4, were identified family single patient Finnish origin (p.R1460Q) proband United States...
Abstract High-throughput DNA sequencing is increasingly employed to diagnose single gene neurological and neuromuscular disorders. Large volumes of data present new challenges in interpretation its useful translation into clinical genetic counselling for families. Even when a plausible identified with confidence, the significance inheritance pattern variants can be challenging. We report our approach evaluating skeletal muscle chloride channel ClC-1 223 probands myotonia congenita as an...
ABSTRACT Background This study aimed to determine the role of five new rare SCN4A variants suspected cause paramyotonia or myotonic disorder. Methods Ten patients from seven families underwent clinical, neurophysiological, imaging, and muscle biopsy examinations. Genetic studies were performed with targeted sequencing all known myopathy genes. Functional changes resulting these studied HEK293T cells, by using a whole‐cell patch clamp. Results Five identified: c.662 T > C p.(F221S),...
Potencies of compounds blocking K(V)11.1 [human ether-ago-go-related gene (hERG)] are commonly assessed using cell lines expressing the Caucasian wild-type (WT) variant. Here we tested whether such potencies would be different for hERG single nucleotide polymorphisms (SNPs).SNPs (R176W, R181Q, Del187-189, P347S, K897T, A915V, P917L, R1047L, A1116V) and a binding-site mutant (Y652A) were expressed in Tet-On CHO-K1 cells. [mean IC(50); lower/upper 95% confidence limit (CL)] 48 blockers was...
Significance Voltage-gated ion channels contain domains that have discrete functionalities. The central pore domain allows current flow and provides selectivity, whereas peripherally located voltage-sensing (VSDs) are needed for voltage-dependent gating. Certain mutations trigger a leak through VSDs, known as gating current. Hypokalemic periodic paralysis (HypoPP) type 2 is caused by in the skeletal muscle voltage-gated sodium channel Na V 1.4 neutralize positive charges S4 segments of VSDs....
Mutations in the skeletal muscle channel (SCN4A), encoding Nav1.4 voltage-gated sodium channel, are causative of a variety channelopathies, including non-dystrophic myotonias and periodic paralysis. The effects many these mutations on function have been characterized both vitro vivo. However, little is known about consequences SCN4A downstream from their impact electrophysiology channel. Here we report discovery novel mutation (c.1762A>G; p.I588V) patient with myotonia paralysis, located...
OBJECTIVE Two novel mutations (E1506D, E1506G) in the nucleotide-binding domain 2 (NBD2) of ATP-sensitive K+ channel (KATP channel) sulfonylurea receptor 1 (SUR1) subunit were detected heterozygously patients with neonatal diabetes. A mutation at same residue (E1506K) was previously shown to cause congenital hyperinsulinemia. We sought understand why can either diabetes or RESEARCH DESIGN AND METHODS Neonatal diabetic sequenced for ABCC8 and KCNJ11 (Kir6.2). Wild-type mutant KATP channels...
Abstract Dominantly inherited channelopathies of the skeletal muscle voltage-gated sodium channel Na V 1.4 include hypokalaemic and hyperkalaemic periodic paralysis (hypoPP hyperPP) myotonia. HyperPP myotonia are caused by overactivity overlap clinically. Instead, hypoPP is gating pore currents through voltage sensing domains (VSDs) seldom co-exists clinically with Recessive loss-of-function mutations have been described in congenital myopathy myasthenic syndromes. We report two families...