Pathophysiological Mechanisms of Dominant and Recessive GLRA1 Mutations in Hyperekplexia

被引:101
|
作者
Chung, Seo-Kyung [1 ]
Vanbellinghen, Jean-Francois [2 ,3 ]
Mullins, Jonathan G. L. [1 ]
Robinson, Angela [1 ]
Hantke, Janina [4 ]
Hammond, Carrie L. [1 ]
Gilbert, Daniel F. [5 ,6 ]
Freilinger, Michael [7 ]
Ryan, Monique [8 ]
Kruer, Michael C. [9 ,10 ]
Masri, Amira [11 ]
Gurses, Candan [12 ]
Ferrie, Colin [13 ]
Harvey, Kirsten [4 ]
Shiang, Rita [14 ]
Christodoulou, John [15 ,16 ]
Andermann, Frederick [17 ]
Andermann, Eva [17 ]
Thomas, Rhys H. [1 ]
Harvey, Robert J. [4 ]
Lynch, Joseph W. [5 ,6 ]
Rees, Mark I. [1 ]
机构
[1] Swansea Univ, Inst Life Sci, Sch Med, Swansea SA2 8PP, W Glam, Wales
[2] Univ Liege, Genet Mol Lab, B-4000 Sart Tilman Par Liege, Belgium
[3] Ctr Hosp Univ Tour Pathol B23 3, B-4000 Sart Tilman Par Liege, Belgium
[4] Univ London, Sch Pharm, Dept Pharmacol, London WC1N 1AX, England
[5] Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia
[6] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia
[7] Med Univ Vienna, Dept Pediat & Adolescent Med, A-1090 Vienna, Austria
[8] Royal Childrens Hosp, Murdoch Childrens Res Inst, Childrens Neurosci Ctr, Parkville, Vic 3052, Australia
[9] Oregon Hlth & Sci Univ, Child Dev & Rehabil Ctr, Div Dev Pediat, Portland, OR 97239 USA
[10] Oregon Hlth & Sci Univ, Child Dev & Rehabil Ctr, Div Pediat Neurol, Portland, OR 97239 USA
[11] Univ Jordan, Fac Med, Dept Pediat, Amman 11942, Jordan
[12] Istanbul Univ, Dept Neurol, TR-34390 Istanbul, Turkey
[13] Leeds Gen Infirm, Dept Paediat Neurol, Leeds LS2 9NS, W Yorkshire, England
[14] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA 23298 USA
[15] Childrens Hosp, Western Sydney Genet Program, Westmead, NSW 2145, Australia
[16] Univ Sydney, Sydney Med Sch, Disciplines Paediat & Child Hlth & Genet Med, Sydney, NSW 2145, Australia
[17] McGill Univ, Montreal Neurol Hosp & Inst, Montreal, PQ H3A 2B4, Canada
来源
JOURNAL OF NEUROSCIENCE | 2010年 / 30卷 / 28期
基金
英国医学研究理事会;
关键词
INHIBITORY GLYCINE RECEPTOR; BETA-SUBUNIT; COMPOUND HETEROZYGOSITY; ACETYLCHOLINE-RECEPTOR; TRANSMEMBRANE DOMAIN; ALPHA-1; SUBUNIT; BINDING; IDENTIFICATION; DETERMINANT; PICROTOXIN;
D O I
10.1523/JNEUROSCI.1763-10.2010
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Hyperekplexia is a rare, but potentially fatal, neuromotor disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden, unexpected auditory or tactile stimuli. This disorder is primarily caused by inherited mutations in the genes encoding the glycine receptor (GlyR) alpha 1 subunit (GLRA1) and the presynaptic glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of GLRA1 in 88 new unrelated human hyperekplexia patients revealed 19 sequence variants in 30 index cases, of which 21 cases were inherited in recessive or compound heterozygote modes. This indicates that recessive hyperekplexia is far more prevalent than previous estimates. From the 19 GLRA1 sequence variants, we have investigated the functional effects of 11 novel and 2 recurrent mutations. The expression levels and functional properties of these hyperekplexia mutants were analyzed using a high-content imaging system and patch-clamp electrophysiology. When expressed in HEK293 cells, either as homomeric alpha 1 or heteromeric alpha 1 beta GlyRs, subcellular localization defects were the major mechanism underlying recessive mutations. However, mutants without trafficking defects typically showed alterations in the glycine sensitivity suggestive of disrupted receptor function. This study also reports the first hyperekplexia mutation associated with a GlyR leak conductance, suggesting tonic channel opening as a new mechanism in neuronal ligand-gated ion channels.
引用
收藏
页码:9612 / 9620
页数:9
相关论文
共 50 条
  • [31] Four Turkish families with hyperekplexia: A missense mutation and the exon 1-7 deletion in the GLRA1 gene
    Tezen, Didem
    Simsir, Gulsah
    cokar, Ozlem
    Demirbilek, Veysi
    Basak, A. Nazli
    Yapici, Zuhal
    PARKINSONISM & RELATED DISORDERS, 2022, 105 : 128 - 131
  • [32] Novel GLRA1 missense mutation (P250T) in dominant hyperekplexia defines an intracellular determinant of glycine receptor channel gating
    Saul, B
    Kuner, T
    Sobetzko, D
    Brune, W
    Hanefeld, F
    Meinck, HM
    Becker, CM
    JOURNAL OF NEUROSCIENCE, 1999, 19 (03): : 869 - 877
  • [33] A NEW MISSENSE MUTATION IN EXON-6 OF THE GLYCINE RECEPTOR (GLRA1) GENE IN HEREDITARY HYPEREKPLEXIA
    MILANI, N
    DALPRA, L
    DELPRETE, L
    ZANINI, R
    LARIZZA, L
    AMERICAN JOURNAL OF HUMAN GENETICS, 1995, 57 (04) : 1274 - 1274
  • [34] A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia
    Tiina Heinonen
    Thomas Flegel
    Hanna Müller
    Alexandra Kehl
    Sruthi Hundi
    Kaspar Matiasek
    Andrea Fischer
    Jonas Donner
    Oliver P. Forman
    Hannes Lohi
    Marjo K. Hytönen
    Human Genetics, 2023, 142 : 1221 - 1230
  • [35] A novel compound mutation in GLRA1 cause hyperekplexia in a Chinese boy- a case report and review of the literature
    Yang, Zhiliang
    Sun, Guilian
    Yao, Fang
    Tao, Dongying
    Zhu, Binlu
    BMC MEDICAL GENETICS, 2017, 18
  • [36] A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia
    Heinonen, Tiina
    Flegel, Thomas
    Mueller, Hanna
    Kehl, Alexandra
    Hundi, Sruthi
    Matiasek, Kaspar
    Fischer, Andrea
    Donner, Jonas
    Forman, Oliver P.
    Lohi, Hannes
    Hytoenen, Marjo K.
    HUMAN GENETICS, 2023, 142 (08) : 1221 - 1230
  • [37] The novel hyperekplexia allele GLRA1(S267N) affects the ethanol site of the glycine receptor
    Kristina Becker
    Hans-Georg Breitinger
    Andreas Humeny
    Hans-Michael Meinck
    Bernd Dietz
    Fuat Aksu
    Cord-Michael Becker
    European Journal of Human Genetics, 2008, 16 : 223 - 228
  • [38] The novel hyperekplexia allele GLRA1(S267N) affects the ethanol site of the glycine receptor
    Becker, Kristina
    Breitinger, Hans-Georg
    Humeny, Andreas
    Meinck, Hans-Michael
    Dietz, Bernd
    Aksu, Fuat
    Becker, Cord-Michael
    EUROPEAN JOURNAL OF HUMAN GENETICS, 2008, 16 (02) : 223 - 228
  • [39] Novel mutation of GLRA1 in Omani families with hyperekplexia and mild mental retardation (vol 46, pg 89, 2013)
    Al-Futaisi, Amna Mohammed
    Al-Kindi, Mohammed Nasser
    Al-Maawali, Almundher
    Koul, Roshan Lal
    Al-Adawi, Samir
    Al-Yahyaee, Said Ali
    PEDIATRIC NEUROLOGY, 2014, 50 (04) : 438 - 438
  • [40] Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias
    Wollnik, B
    Schroeder, BC
    Kubisch, C
    Esperer, HD
    Wieacker, P
    Jentsch, TJ
    HUMAN MOLECULAR GENETICS, 1997, 6 (11) : 1943 - 1949