DOCSLIB.ORG

Genetic Neurological Channelopathies: Molecular Genetics and Clinical Phenotypes J Spillane,1,2 D M Kullmann,2,3 M G Hanna2,3

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genetic Neurological Channelopathies: Molecular Genetics and Clinical Phenotypes J Spillane,1,2 D M Kullmann,2,3 M G Hanna2,3 JNNP Online First, published on November 11, 2015 as 10.1136/jnnp-2015-311233 Neurogenetics J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2015-311233 on 11 November 2015. Downloaded from REVIEW Genetic neurological channelopathies: molecular genetics and clinical phenotypes J Spillane,1,2 D M Kullmann,2,3 M G Hanna2,3 ▸ Additional material is ABSTRACT channel kinetics and membrane stabilisation2 published online only. To view Evidence accumulated over recent years has shown that (figure 1). please visit the journal online (http://dx.doi.org/10.1136/ genetic neurological channelopathies can cause many Although ion channels are essential for the jnnp-2015-311233). different neurological diseases. Presentations relating to normal function of all eukaryotic cells, they are the brain, spinal cord, peripheral nerve or muscle mean particularly important in the nervous system for 1Royal Free Hospital Foundation Trust London, that channelopathies can impact on almost any area of the generation, repression and propagation of London, UK neurological practice. Typically, neurological action potentials. Ion channels are often highly 2MRC Centre for channelopathies are inherited in an autosomal dominant selective for a particular ionic species, for example, Neuromuscular Disease, UCL, fashion and cause paroxysmal disturbances of sodium, potassium or calcium. The opening of London, UK 3UCL, Institute of Neurology, neurological function, although the impairment of sodium channels leads to depolarisation of neurons London, UK function can become fixed with time. These disorders whereas potassium channel opening leads to hyper- are individually rare, but an accurate diagnosis is polarisation, as does the opening of chloride chan- Correspondence to important as it has genetic counselling and often nels in adult neurons. The opening of calcium Professor MG Hanna, MRC treatment implications. Furthermore, the study of less channels causes membrane depolarisation, but Centre for Neuromuscular Diseases, P.O. Box 102, common ion channel mutation-related diseases has calcium ions also have more important roles as 3 National Hospital for increased our understanding of pathomechanisms that is second messengers. Hence, loss of function muta- Neurology and Neurosurgery, relevant to common neurological diseases such as tions in potassium or chloride channels or gain of Queen Square, London WC1N migraine and epilepsy. Here, we review the molecular function mutations should lead to disorders charac- 3BG, UK; [email protected] genetic and clinical features of inherited neurological terised by hyperexcitability, such as epilepsy. Received 11 May 2015 channelopathies. However, the effect of a mutation depends on the copyright. Revised 16 August 2015 specific neuronal circuitry involved. For example, a Accepted 13 September 2015 mutation that causes a gain of function effect in inhibitory interneurons can decrease excitability.3 INTRODUCTION Given their importance in neuronal excitability Inherited disorders of ion channel function—the and synaptic transmission through the central and ‘genetic channelopathies’ are a rapidly expanding peripheral nervous systems, it is not surprising that group of neurological disorders and are implicated mutations in ion channel genes can lead to disease. in many areas of neurological practice. Although Many of the mutations that have been associated the inherited channelopathies are individually rare, with ion channel disorders are missense mutations the study of these conditions is contributing to our that affect channel kinetics. However, inherited understanding of pathomechanisms of neurological mutations and chromosomal rearrangements can disease in general. affect any stage of ion channel biogenesis, including http://jnnp.bmj.com/ Ion channels are specialised pore-forming pro- transcription, mRNA processing, splicing, transla- teins that allow the passage of certain ions across tion, folding and trafficking, as well as subunit the lipid bilayer of the cell membrane. They are assembly. typically divided into two broad categories accord- Inherited disorders of ion channels are typically ing to their method of activation—voltage or inherited in an autosomal dominant fashion, ligand gated. The ‘gating’ of ion channels by trans- although there are exceptions, and can cause a membrane voltage changes or specific receptor variety of neurological syndromes. Typically, symp- on September 29, 2021 by guest. Protected ligands, such as acetylcholine (ACh), together with toms begin relatively early in life and are paroxys- their selectivity for distinct ion species, underlies mal or episodic, although a fixed deficit may the coordination of ion fluxes during action poten- develop with time. These attacks or paroxysms are tials or following neurotransmitter release.1 often precipitated by various triggers. Stress, of Most ion channels have a similar basic structure some form, is a frequent trigger, whereas certain —for example, all voltage-gated ion channels have triggers are disease specific, such as heat in primary a large pore-forming subunit—the α subunit, com- erythromelalgia (PE), or rest after exercise or a posed of four homologous domains (I–IV)—each carbohydrate load in periodic paralysis. Mutations composed of six transmembrane segments (S1–S6). in ion channels can alter channel function such that To cite: Spillane J, In all cation channels, the S4 segments contain homoeostasis cannot be maintained in the presence Kullmann DM, Hanna MG. J between four and eight positively charged residues of certain stimuli that would usually be innocuous.4 Neurol Neurosurg Psychiatry Published Online First: conferring voltage dependence, and the S5-S6 In this review, we describe the clinical character- [please include Day Month loops form the ion pore. Ion channels are also istics and genetics of inherited channelopathies of Year] doi:10.1136/jnnp- composed of several accessory subunits that may be the brain, spinal cord, peripheral nerve and muscle 2015-311233 cytoplasmic or extracellular that have roles in (see online supplemental figure S1). Spillane J, et al. J Neurol Neurosurg Psychiatry 2015;0:1–12. doi:10.1136/jnnp-2015-311233 1 Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence. Neurogenetics J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2015-311233 on 11 November 2015. Downloaded from Figure 1 (A) Structure of the α subunit of the voltage-gated sodium channel NaV1.1 encoded by SCN1A. The subunit is composed of four domains (I–IV), which are each composed of six transmembrane subunits (S1–S6)—the positive gating charges in the S4 subunit are marked as is the pore region (between S5 and S6). (B) Schematic representation of ion channel in open and closed states. CHANNELOPATHIES OF THE CENTRAL NERVOUS SYSTEM Mutations in SCN8A as well as KNCQ2 have been associated – Epilepsy with severe epileptic encephalopathies.20 22 Some cases of Although rare, inherited channelopathies account for a substan- DEND syndrome, (developmental delay, epilepsy and neonatal tial fraction of Mendelian epilepsy syndromes and can cause a diabetes) are caused by mutations in KCNJ11 which encodes variety of epilepsy types ranging from severe infantile encephal- the Kir 6.2 subunit of the ATP-sensitive potassium channel.23 24 opathies to relatively benign focal seizures (table 1). Generalised epilepsy syndromes Channelopathies associated with epileptic encephalopathies Generalised epilepsy with febrile seizures plus is a genetically Early onset epileptic encephalopathies are generally severe epilepsy and clinically heterogeneous familial epilepsy syndrome.25 copyright. syndromes that often have a poor neurodevelopmental outcome. Individuals develop febrile seizures early in life that persist Severe myoclonic epilepsy of infancy, also known as Dravet beyond the age of 6 years. Numerous different genes have been syndrome, manifests as intractable seizures that begin in the first implicated; namely the sodium channel genes SCN1A, SCN1B, year of life associated with developmental regression and cogni- SCN2A and the GABAA receptor subunit genes GABRG2 and – tive impairment.56Missense or nonsense mutations in the GABRD.26 30 SCNA1 gene which encodes the pore-forming unit of the fast Benign familial neonatal infantile seizures is an epilepsy syn- sodium channel NaV1.1 are present in over 80% of cases and drome characterised by sudden onset and subsequent remission are typically de novo, leading to haploinsufficiency.78More of seizures in infancy.31 32 It is caused by missense mutations in rarely, mutations in other genes including SCN1B and SCN2A the SCN2A gene.8 Benign familial neonatalconvulsions (BFNC) have been found, as well as mutations in the GABAA receptor is a similar syndrome characterised by brief seizures, occurring – subunit gene GABRG2.9 11 For some time, it was not under- on the second or third day after birth that usually terminate stood how a mutation in a sodium channel leading to haploin- within 6 weeks with normal neurological development.33 34 It http://jnnp.bmj.com/ sufficiency and reduced function could cause hyperexcitability. can be caused by loss of function mutations in two potassium However, it was subsequently found that NaV1.1 channels have channel genes, KCNQ2 and KCNQ3, which code for the potas- 35–38 an important role in GABAergic inhibitory neurons, thus loss of sium channel subunits KV7.2 and 7.3, respectively. Proteins function of these channels leads to hypoexcitability
Load more

Recommended publications
  • Spectrum of CLCN1 Mutations in Patients with Myotonia Congenita in Northern Scandinavia
    European Journal of Human Genetics (2001) 9, 903 ± 909 ã 2001 Nature Publishing Group All rights reserved 1018-4813/01 $15.00 www.nature.com/ejhg ARTICLE Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia Chen Sun*,1, Lisbeth Tranebjñrg*,1, Torberg Torbergsen2,GoÈsta Holmgren3 and Marijke Van Ghelue1,4 1Department of Medical Genetics, University Hospital of Tromsù, Tromsù, Norway; 2Department of Neurology, University Hospital of Tromsù, Tromsù, Norway; 3Department of Clinical Genetics, University Hospital of UmeaÊ, UmeaÊ,Sweden;4Department of Biochemistry, Section Molecular Biology, University of Tromsù, Tromsù, Norway Myotonia congenita is a non-dystrophic muscle disorder affecting the excitability of the skeletal muscle membrane. It can be inherited either as an autosomal dominant (Thomsen's myotonia) or an autosomal recessive (Becker's myotonia) trait. Both types are characterised by myotonia (muscle stiffness) and muscular hypertrophy, and are caused by mutations in the muscle chloride channel gene, CLCN1. At least 50 different CLCN1 mutations have been described worldwide, but in many studies only about half of the patients showed mutations in CLCN1. Limitations in the mutation detection methods and genetic heterogeneity might be explanations. In the current study, we sequenced the entire CLCN1 gene in 15 Northern Norwegian and three Northern Swedish MC families. Our data show a high prevalence of myotonia congenita in Northern Norway similar to Northern Finland, but with a much higher degree of mutation heterogeneity. In total, eight different mutations and three polymorphisms (T87T, D718D, and P727L) were detected. Three mutations (F287S, A331T, and 2284+5C4T) were novel while the others (IVS1+3A4T, 979G4A, F413C, A531V, and R894X) have been reported previously.
    [Show full text]
  • Paramyotonia Congenita
    Paramyotonia congenita Description Paramyotonia congenita is a disorder that affects muscles used for movement (skeletal muscles). Beginning in infancy or early childhood, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Myotonia causes muscle stiffness that typically appears after exercise and can be induced by muscle cooling. This stiffness chiefly affects muscles in the face, neck, arms, and hands, although it can also affect muscles used for breathing and muscles in the lower body. Unlike many other forms of myotonia, the muscle stiffness associated with paramyotonia congenita tends to worsen with repeated movements. Most people—even those without muscle disease—feel that their muscles do not work as well when they are cold. This effect is dramatic in people with paramyotonia congenita. Exposure to cold initially causes muscle stiffness in these individuals, and prolonged cold exposure leads to temporary episodes of mild to severe muscle weakness that may last for several hours at a time. Some older people with paramyotonia congenita develop permanent muscle weakness that can be disabling. Frequency Paramyotonia congenita is an uncommon disorder; it is estimated to affect fewer than 1 in 100,000 people. Causes Mutations in the SCN4A gene cause paramyotonia congenita. This gene provides instructions for making a protein that is critical for the normal function of skeletal muscle cells. For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by the flow of positively charged atoms (ions), including sodium, into skeletal muscle cells. The SCN4A protein forms channels that control the flow of sodium ions into these cells.
    [Show full text]
  • Spinocerebellar Ataxia Genetic Testing
    Lab Management Guidelines V1.0.2020 Spinocerebellar Ataxia Genetic Testing MOL.TS.311.A v1.0.2020 Introduction Spinocerebellar ataxia (SCA) genetic testing is addressed by this guideline. Procedures addressed The inclusion of any procedure code in this table does not imply that the code is under management or requires prior authorization. Refer to the specific Health Plan's procedure code list for management requirements. Procedures addressed by this Procedure codes guideline ATXN1 gene analysis, evaluation to detect 81178 abnormal (eg,expanded) allele ATXN2 gene analysis, evaluation to detect 81179 abnormal (eg,expanded) allele ATXN3 gene analysis, evaluation to detect 81180 abnormal (eg,expanded) allele ATXN7 gene analysis, evaluation to detect 81181 abnormal (eg,expanded) allele ATXN8 gene analysis, evaluation to detect 81182 abnormal (eg, expanded) alleles ATXN10 gene analysis, evaluation to 81183 detect abnormal (eg, expanded) alleles CACNA1A gene analysis; evaluation to 81184 detect abnormal (eg, expanded) alleles CACNA1A gene analysis; full gene 81185 sequence CACNA1A gene analysis; known familial 81186 variant PPP2R2B gene analysis, evaluation to 81343 detect abnormal (eg, expanded) alleles TBP gene analysis, evaluation to detect 81344 abnormal (eg, expanded) alleles Unlisted molecular pathology procedure 81479 © 2020 eviCore healthcare. All Rights Reserved. 1 of 15 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines V1.0.2020 What is spinocerebellar ataxia Definition Spinocerebrallar ataxias (SCA) are a group of autosomal dominant ataxias that have a range of phenotypes. There are various subtypes of SCA, which are denoted by numbers (e.g. SCA1, SCA3, etc.) Incidence and Prevalence The prevalence of autosomal dominant cerebellar ataxias, as a whole, is 1-5:100,000.1 SCA3 is the most common autosomal dominant form of ataxia.
    [Show full text]
  • Experiences of Rare Diseases: an Insight from Patients and Families
    Experiences of Rare Diseases: An Insight from Patients and Families Unit 4D, Leroy House 436 Essex Road London N1 3QP tel: 02077043141 fax: 02073591447 [email protected] www.raredisease.org.uk By Lauren Limb, Stephen Nutt and Alev Sen - December 2010 Web and press design www.raredisease.org.uk WordsAndPeople.com About Rare Disease UK Rare Disease UK (RDUK) is the national alliance for people with rare diseases and all who support them. Our membership is open to all and includes patient organisations, clinicians, researchers, academics, industry and individuals with an interest in rare diseases. RDUK was established by Genetic RDUK is campaigning for a Alliance UK, the national charity strategy for integrated service of over 130 patient organisations delivery for rare diseases. This supporting all those affected by would coordinate: genetic conditions, in conjunction with other key stakeholders | Research in November 2008 following the European Commission’s | Prevention and diagnosis Communication on Rare Diseases: | Treatment and care Europe’s Challenges. | Information Subsequently RDUK successfully | Commissioning and planning campaigned for the adoption of the Council of the European into one cohesive strategy for all Union’s Recommendation on patients affected by rare disease in an action in the field of rare the UK. As well as securing better diseases. The Recommendation outcomes for patients, a strategy was adopted unanimously by each would enable the most effective Member State of the EU (including use of NHS resources. the
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Amino Acid Disorders 105
    AMINO ACID DISORDERS 105 Massaro, A. S. (1995). Trypanosomiasis. In Guide to Clinical tions in biological fluids relatively easy. These Neurology (J. P. Mohrand and J. C. Gautier, Eds.), pp. 663– analyzers separate amino acids either by ion-ex- 667. Churchill Livingstone, New York. Nussenzweig, V., Sonntag, R., Biancalana, A., et al. (1953). Ac¸a˜o change chromatography or by high-pressure liquid de corantes tri-fenil-metaˆnicos sobre o Trypanosoma cruzi in chromatography. The results are plotted as a graph vitro: Emprego da violeta de genciana na profilaxia da (Fig. 1). The concentration of each amino acid can transmissa˜o da mole´stia de chagas por transfusa˜o de sangue. then be calculated from the size of the corresponding O Hospital (Rio de Janeiro) 44, 731–744. peak on the graph. Pagano, M. A., Segura, M. J., DiLorenzo, G. A., et al. (1999). Cerebral tumor-like American trypanosomiasis in Most amino acid disorders can be diagnosed by acquired immunodeficiency syndrome. Ann. Neurol. 45, measuring the concentrations of amino acids in 403–406. blood plasma; however, some disorders of amino Rassi, A., Trancesi, J., and Tranchesi, B. (1982). Doenc¸ade acid transport are more easily recognized through the Chagas. In Doenc¸as Infecciosas e Parasita´rias (R. Veroesi, Ed.), analysis of urine amino acids. Therefore, screening 7th ed., pp. 674–712. Guanabara Koogan, Sa˜o Paulo, Brazil. Spina-Franc¸a, A., and Mattosinho-Franc¸a, L. C. (1988). for amino acid disorders is best done using both South American trypanosomiasis (Chagas’ disease). In blood and urine specimens. Occasionally, analysis of Handbook of Clinical Neurology (P.
    [Show full text]
  • Protein Identities in Evs Isolated from U87-MG GBM Cells As Determined by NG LC-MS/MS
    Protein identities in EVs isolated from U87-MG GBM cells as determined by NG LC-MS/MS. No. Accession Description Σ Coverage Σ# Proteins Σ# Unique Peptides Σ# Peptides Σ# PSMs # AAs MW [kDa] calc. pI 1 A8MS94 Putative golgin subfamily A member 2-like protein 5 OS=Homo sapiens PE=5 SV=2 - [GG2L5_HUMAN] 100 1 1 7 88 110 12,03704523 5,681152344 2 P60660 Myosin light polypeptide 6 OS=Homo sapiens GN=MYL6 PE=1 SV=2 - [MYL6_HUMAN] 100 3 5 17 173 151 16,91913397 4,652832031 3 Q6ZYL4 General transcription factor IIH subunit 5 OS=Homo sapiens GN=GTF2H5 PE=1 SV=1 - [TF2H5_HUMAN] 98,59 1 1 4 13 71 8,048185945 4,652832031 4 P60709 Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 - [ACTB_HUMAN] 97,6 5 5 35 917 375 41,70973209 5,478027344 5 P13489 Ribonuclease inhibitor OS=Homo sapiens GN=RNH1 PE=1 SV=2 - [RINI_HUMAN] 96,75 1 12 37 173 461 49,94108966 4,817871094 6 P09382 Galectin-1 OS=Homo sapiens GN=LGALS1 PE=1 SV=2 - [LEG1_HUMAN] 96,3 1 7 14 283 135 14,70620005 5,503417969 7 P60174 Triosephosphate isomerase OS=Homo sapiens GN=TPI1 PE=1 SV=3 - [TPIS_HUMAN] 95,1 3 16 25 375 286 30,77169764 5,922363281 8 P04406 Glyceraldehyde-3-phosphate dehydrogenase OS=Homo sapiens GN=GAPDH PE=1 SV=3 - [G3P_HUMAN] 94,63 2 13 31 509 335 36,03039959 8,455566406 9 Q15185 Prostaglandin E synthase 3 OS=Homo sapiens GN=PTGES3 PE=1 SV=1 - [TEBP_HUMAN] 93,13 1 5 12 74 160 18,68541938 4,538574219 10 P09417 Dihydropteridine reductase OS=Homo sapiens GN=QDPR PE=1 SV=2 - [DHPR_HUMAN] 93,03 1 1 17 69 244 25,77302971 7,371582031 11 P01911 HLA class II histocompatibility antigen,
    [Show full text]
  • Hypokalemic Periodic Paralysis - an Owner's Manual
    Hypokalemic periodic paralysis - an owner's manual Michael M. Segal MD PhD1, Karin Jurkat-Rott MD PhD2, Jacob Levitt MD3, Frank Lehmann-Horn MD PhD2 1 SimulConsult Inc., USA 2 University of Ulm, Germany 3 Mt. Sinai Medical Center, New York, USA 5 June 2009 This article focuses on questions that arise about diagnosis and treatment for people with hypokalemic periodic paralysis. We will focus on the familial form of hypokalemic periodic paralysis that is due to mutations in one of various genes for ion channels. We will only briefly mention other �secondary� forms such as those due to hormone abnormalities or due to kidney disorders that result in chronically low potassium levels in the blood. One can be the only one in a family known to have familial hypokalemic periodic paralysis if there has been a new mutation or if others in the family are not aware of their illness. For more general background about hypokalemic periodic paralysis, a variety of descriptions of the disease are available, aimed at physicians or patients. Diagnosis What tests are used to diagnose hypokalemic periodic paralysis? The best tests to diagnose hypokalemic periodic paralysis are measuring the blood potassium level during an attack of paralysis and checking for known gene mutations. Other tests sometimes used in diagnosing periodic paralysis patients are the Compound Muscle Action Potential (CMAP) and Exercise EMG; further details are here. The most definitive way to make the diagnosis is to identify one of the calcium channel gene mutations or sodium channel gene mutations known to cause the disease. However, known mutations are found in only 70% of people with hypokalemic periodic paralysis (60% have known calcium channel mutations and 10% have known sodium channel mutations).
    [Show full text]
  • Difference in Allelic Expression of the CLCN1 Gene and the Possible Influence on the Myotonia Congenita Phenotype
    European Journal of Human Genetics (2004) 12, 738–743 & 2004 Nature Publishing Group All rights reserved 1018-4813/04 $30.00 www.nature.com/ejhg ARTICLE Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype Morten Dun1*, Eskild Colding-Jrgensen2, Morten Grunnet3,5, Thomas Jespersen3, John Vissing4 and Marianne Schwartz1 1Department of Clinical Genetics, 4062, University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; 2Department of Clinical Neurophysiology 3063,University Hospital, Rigshospitalet, Blegdamsvej 9, DK- 2100 Copenhagen, Denmark; 3Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark; 4Department of Neurology and The Copenhagen Muscle Research Center, University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark Mutations in the CLCN1 gene, encoding a muscle-specific chloride channel, can cause either recessive or dominant myotonia congenita (MC). The recessive form, Becker’s myotonia, is believed to be caused by two loss-of-function mutations, whereas the dominant form, Thomsen’s myotonia, is assumed to be a consequence of a dominant-negative effect. However, a subset of CLCN1 mutations can cause both recessive and dominant MC. We have identified two recessive and two dominant MC families segregating the common R894X mutation. Real-time quantitative RT-PCR did not reveal any obvious association between the total CLCN1 mRNA level in muscle and the mode of inheritance, but the dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele. Variation in allelic expression has not previously been described for CLCN1, and our finding suggests that allelic variation may be an important modifier of disease progression in myotonia congenita.
    [Show full text]
  • Restoration of Epithelial Sodium Channel Function by Synthetic Peptides in Pseudohypoaldosteronism Type 1B Mutants
    ORIGINAL RESEARCH published: 24 February 2017 doi: 10.3389/fphar.2017.00085 Restoration of Epithelial Sodium Channel Function by Synthetic Peptides in Pseudohypoaldosteronism Type 1B Mutants Anita Willam 1*, Mohammed Aufy 1, Susan Tzotzos 2, Heinrich Evanzin 1, Sabine Chytracek 1, Sabrina Geppert 1, Bernhard Fischer 2, Hendrik Fischer 2, Helmut Pietschmann 2, Istvan Czikora 3, Rudolf Lucas 3, Rosa Lemmens-Gruber 1 and Waheed Shabbir 1, 2 1 Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria, 2 APEPTICO GmbH, Vienna, Austria, 3 Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, USA Edited by: The synthetically produced cyclic peptides solnatide (a.k.a. TIP or AP301) and its Gildas Loussouarn, congener AP318, whose molecular structures mimic the lectin-like domain of human University of Nantes, France tumor necrosis factor (TNF), have been shown to activate the epithelial sodium Reviewed by: channel (ENaC) in various cell- and animal-based studies. Loss-of-ENaC-function Stephan Kellenberger, University of Lausanne, Switzerland leads to a rare, life-threatening, salt-wasting syndrome, pseudohypoaldosteronism type Yoshinori Marunaka, 1B (PHA1B), which presents with failure to thrive, dehydration, low blood pressure, Kyoto Prefectural University of Medicine, Japan anorexia and vomiting; hyperkalemia, hyponatremia and metabolic acidosis suggest *Correspondence: hypoaldosteronism, but plasma aldosterone and renin activity are high. The aim of Anita Willam the present study was to investigate whether the ENaC-activating effect of solnatide [email protected] and AP318 could rescue loss-of-function phenotype of ENaC carrying mutations at + Specialty section: conserved amino acid positions observed to cause PHA1B.
    [Show full text]
  • Characterization of Zebrafish GABAA Receptor Subunits
    www.nature.com/scientificreports OPEN Characterization of zebrafsh GABAA receptor subunits Kenichiro Sadamitsu, Leona Shigemitsu, Marina Suzuki, Daishi Ito, Makoto Kashima & Hiromi Hirata* γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, exerts its efect through the activation of GABA receptors. GABAA receptors are ligand-gated chloride channels composed of fve subunit proteins. Mammals have 19 diferent GABAA receptor subunits (α1–6, β1–3, γ1–3, δ, ε, π, θ, and ρ1–3), the physiological properties of which have been assayed by electrophysiology. However, the evolutionary conservation of the physiological characteristics of diverged GABAA receptor subunits remains unclear. Zebrafsh have 23 subunits (α1, α2a, α2b, α3–5, α6a, α6b, β1–4, γ1–3, δ, π, ζ, ρ1, ρ2a, ρ2b, ρ3a, and ρ3b), but the electrophysiological properties of these subunits have not been explored. In this study, we cloned the coding sequences for zebrafsh GABAA receptor subunits and investigated their expression patterns in larval zebrafsh by whole- mount in situ hybridization. We also performed electrophysiological recordings of GABA-evoked currents from Xenopus oocytes injected with one or multiple zebrafsh GABAA receptor subunit cRNAs and calculated the half-maximal efective concentrations (EC50s) for each. Our results revealed the spatial expressions and electrophysiological GABA sensitivities of zebrafsh GABAA receptors, suggesting that the properties of GABAA receptor subunits are conserved among vertebrates. γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system of vertebrates, 1 controls the excitability of neural networks mainly through GABA A receptors . Te GABAA receptor mediates two types of inhibition, known as phasic and tonic inhibition2.
    [Show full text]
  • Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed Hipscs To
    Hindawi Publishing Corporation Stem Cells International Volume 2013, Article ID 784629, 25 pages http://dx.doi.org/10.1155/2013/784629 Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny Leonhard Linta,1 Marianne Stockmann,1 Qiong Lin,2 André Lechel,3 Christian Proepper,1 Tobias M. Boeckers,1 Alexander Kleger,3 and Stefan Liebau1 1 InstituteforAnatomyCellBiology,UlmUniversity,Albert-EinsteinAllee11,89081Ulm,Germany 2 Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen, Pauwelstrasse 30, 52074 Aachen, Germany 3 Department of Internal Medicine I, Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany Correspondence should be addressed to Alexander Kleger; [email protected] and Stefan Liebau; [email protected] Received 31 January 2013; Accepted 6 March 2013 Academic Editor: Michael Levin Copyright © 2013 Leonhard Linta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ion channels are involved in a large variety of cellular processes including stem cell differentiation. Numerous families of ion channels are present in the organism which can be distinguished by means of, for example, ion selectivity, gating mechanism, composition, or cell biological function. To characterize the distinct expression of this group of ion channels we have compared the mRNA expression levels of ion channel genes between human keratinocyte-derived induced pluripotent stem cells (hiPSCs) and their somatic cell source, keratinocytes from plucked human hair. This comparison revealed that 26% of the analyzed probes showed an upregulation of ion channels in hiPSCs while just 6% were downregulated.
    [Show full text]