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Pesquisa : C10.228.590 [Categoria DeCS]
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  1 / 6 MEDLINE  
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[PMID]:28985719
[Au] Autor:Yang Z; Sun G; Yao F; Tao D; Zhu B
[Ad] Endereço:Department of Pediatrics, The First Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China. sizhewujiu@163.com.
[Ti] Título:A novel compound mutation in GLRA1 cause hyperekplexia in a Chinese boy- a case report and review of the literature.
[So] Source:BMC Med Genet;18(1):110, 2017 Oct 06.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The pathogenesis of hereditary hyperekplexia is thought to involve abnormalities in the glycinergic neurotransmission system, the most of mutations reported in GLRA1. This gene encodes the glycine receptor α1 subunit, which has an extracellular domain (ECD) and a transmembrane domain (TMD) with 4 α-helices (TM1-TM4). CASE PRESENTATION: We investigated the genetic cause of hyperekplexia in a Chinese family with one affected member. Whole-exome sequencing of the 5 candidate genes was performed on the proband patient, and direct sequencing was performed to validate and confirm the detected mutation in other family members. We also review and analyse all reported GLRA1 mutations. The proband had a compound heterozygous GLRA1 mutation that comprised 2 novel GLRA1 missense mutations, C.569C > T (p.T190 M) from the mother and C.1270G > A (p.D424N) from the father. SIFT, Polyphen-2 and MutationTaster analysis identified the mutations as disease-causing, but the parents had no signs of hyperekplexia. The p.T190 M mutation is located in the ECD, while p.D424N is located in TM4. CONCLUSIONS: Our findings contribute to a growing list GLRA1 mutations associated with hyperekplexia and provide new insights into correlations between phenotype and GLRA1 mutations. Some recessive mutations can induce hyperekplexia in combination with other recessive GLRA1 mutations. Mutations in the ECD, TM1, TM1-TM2 loop, TM3, TM3-TM4 loop and TM4 are more often recessive and part of a compound mutation, while those in TM2 and the TM2-TM3 loop are more likely to be dominant hereditary mutations.
[Mh] Termos MeSH primário: Hiperecplexia/genética
Mutação
Receptores da Glicina/genética
[Mh] Termos MeSH secundário: Adolescente
China
Feminino
Loci Gênicos/genética
Seres Humanos
Hiperecplexia/diagnóstico
Hiperecplexia/fisiopatologia
Lactente
Masculino
Linhagem
Fenótipo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Glycine); 0 (glycine receptor alpha1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171008
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0476-6


  2 / 6 MEDLINE  
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[PMID]:28174298
[Au] Autor:Safar F; Hurdiss E; Erotocritou M; Greiner T; Lape R; Irvine MW; Fang G; Jane D; Yu R; Dämgen MA; Biggin PC; Sivilotti LG
[Ad] Endereço:From the Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
[Ti] Título:The Startle Disease Mutation E103K Impairs Activation of Human Homomeric α1 Glycine Receptors by Disrupting an Intersubunit Salt Bridge across the Agonist Binding Site.
[So] Source:J Biol Chem;292(12):5031-5042, 2017 Mar 24.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glycine receptors (GlyR) belong to the pentameric ligand-gated ion channel (pLGIC) superfamily and mediate fast inhibitory transmission in the vertebrate CNS. Disruption of glycinergic transmission by inherited mutations produces startle disease in man. Many startle mutations are in GlyRs and provide useful clues to the function of the channel domains. E103K is one of few startle mutations found in the extracellular agonist binding site of the channel, in loop A of the principal side of the subunit interface. Homology modeling shows that the side chain of Glu-103 is close to that of Arg-131, in loop E of the complementary side of the binding site, and may form a salt bridge at the back of the binding site, constraining its size. We investigated this hypothesis in recombinant human α1 GlyR by site-directed mutagenesis and functional measurements of agonist efficacy and potency by whole cell patch clamp and single channel recording. Despite its position near the binding site, E103K causes hyperekplexia by impairing the efficacy of glycine, its ability to gate the channel once bound, which is very high in wild type GlyR. Mutating Glu-103 and Arg-131 caused various degrees of loss-of-function in the action of glycine, whereas mutations in Arg-131 enhanced the efficacy of the slightly bigger partial agonist sarcosine ( -methylglycine). The effects of the single charge-swapping mutations of these two residues were largely rescued in the double mutant, supporting the possibility that they interact via a salt bridge that normally constrains the efficacy of larger agonist molecules.
[Mh] Termos MeSH primário: Hiperecplexia/genética
Mutação Puntual
Receptores da Glicina/genética
Receptores da Glicina/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Cristalografia por Raios X
Glicina/metabolismo
Células HEK293
Seres Humanos
Hiperecplexia/metabolismo
Modelos Moleculares
Mutagênese Sítio-Dirigida
Receptores da Glicina/química
Sarcosina/metabolismo
Alinhamento de Sequência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Glycine); 0 (glycine receptor alpha1); TE7660XO1C (Glycine); Z711V88R5F (Sarcosine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.767616


  3 / 6 MEDLINE  
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[PMID]:28173650
[Au] Autor:Li H; Yang ZX; Xue J; Qian P; Liu XY
[Ad] Endereço:Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
[Ti] Título:[Clinical and genetic analysis of hyperekplexia in a Chinese child and literature review].
[So] Source:Zhonghua Er Ke Za Zhi;55(2):120-124, 2017 Feb 02.
[Is] ISSN:0578-1310
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:To investigate the clinical and genetic features of a Chinese child with hyperekplexia and review the related literature. The clinical and genetic data of one patient with hyperekplexia, who had visited the department of Pediatrics, Peking University First Hospital in July 2012, were analyzed. "Hyperekplexia" "startle disease" "GLRB" were used as key words to search at CNKI, Wanfang and PubMed from the database from creation to August 2016. The one-year-old female patient showed exaggerated startle reflexes and generalized stiffness in response to external sudden, unexpected stimuli at 2 hours after birth, which existed every day. Her younger twin sister died of severe apnea due to a continuous generalized stiffness at the age of 7 months. Physical examination exhibited the positive nose-tapping reflex. There were no obvious abnormalities in laboratory tests, electroencephalogram (EEG) and neuroimaging tests. The patient was revealed to have compound heterozygous mutations in GLRB gene, c. 298-1G>A (or IVS4-1G>A) inherited from the father and c. 347T>C (p. L116P) inherited from the mother. The mutation L116P in GLRB gene was not reported before. During the follow-up until 5 years old, the girl's symptoms of startle reflexes and generalized stiffness were controlled with clonazepam treatment. Her mental development was normal, but she walked very carefully as wide-based gait to avoid of external sudden stimuli. Literature retrieval obtained 8 reports (all in English) with 39 GLRB-related cases. Combined analysis of the data of the 39 foreign cases and our case showed that the onset age of all 40 cases was in neonatal or and all presented exaggerated startle reflexes and generalized stiffness in response to external stimuli. Other symptoms included neonatal apneas (83%, 20/24), falls (56%, 15/27) and squint (42%, 10/24) etc. EEG (13/13) and brain imaging (90%, 28/31) were normal, or unrelated/nonspecific to hyperekplexia. In the total 17 mutations of GLRB gene found in 28 cases, the most frequent mutations were GLRB gene M177R (9 cases) and IVS5+ 5G>A (5 cases). Most cases (82%, 32/39) had received the treatment of clonazepam. The symptoms of hyperekplexia all could be improved in different degree after treatment, and 84% (32/38) of the cases were completely controlled or only existed exaggerated startle reflexes. The psychomotor development could be normal (13 cases) or retarded (25 cases). The patient presented typical clinical manifestations of hyperekplexia and had a good response to clonazepam. The patient carried GLRB gene mutations found by genetic analysis, and was finally diagnosed with hyperekplexia. The younger twin sister died due to lack of timely diagnosis and treatment, suggesting the significance of early detection and proper treatment for this disease.
[Mh] Termos MeSH primário: Hiperecplexia/genética
[Mh] Termos MeSH secundário: Idade de Início
Grupo com Ancestrais do Continente Asiático
Criança
China
Eletroencefalografia
Feminino
Testes Genéticos
Seres Humanos
Hiperecplexia/diagnóstico
Lactente
Masculino
Mutação
Doenças do Sistema Nervoso
Receptores da Glicina
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Glycine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170727
[Lr] Data última revisão:
170727
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.0578-1310.2017.02.013


  4 / 6 MEDLINE  
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[PMID]:27843043
[Au] Autor:Masri A; Chung SK; Rees MI
[Ad] Endereço:Faculty of Medicine, The University of Jordan, P.O. Box 1612 Code, 11941 Amman, Jordan. Electronic address: masriamira69@hotmail.com.
[Ti] Título:Hyperekplexia: Report on phenotype and genotype of 16 Jordanian patients.
[So] Source:Brain Dev;39(4):306-311, 2017 Apr.
[Is] ISSN:1872-7131
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hyperekplexia, is a rare disorder characterized by excessive startle response to acoustic, visual, or other stimuli. It is inherited in autosomal recessive and dominant pattern. OBJECTIVE: To describe the clinical and genetic features of hyperekplexia in Jordanian patients. METHODS: This retrospective study includes all patients with proved genetic diagnosis of hyperekplexia who presented to our clinic at the Jordan University Hospital from January 2001 through July 2015. RESULTS: A total of 16 children from 12 families were included. The total follow up period ranged from one to eleven years. The majority of the patients (13/16=81.3%) were initially misdiagnosed as epilepsy. All patients had excessive startle response since birth. Tonic-apneic spells occurred in 15/16=93.8% patients. Fourteen patients (45/16=87.5%) received clonazepam. Stopping clonazepam by three years of age failed in 11/14 (78.6%) due to reappearance of tonic-apneic spells (8/14=57.1%), recurrent falling (10/14=71.4%) or due to both reasons (5/14=35.7%). Delayed motor development occurred in 7/16 (43.8%), speech delay in 4/16 (25.0%), global developmental delay in 1/16 (6.3%), and autism spectrum disorder in 1/16 (6.3%) patient. The mode of inheritance is autosomal recessive in all 12/12 (100%) families. Mutations in GLRA1 gene was present in 9/16 (56.3%); the most common mutation was in p.G254D (4/9; 44.5%). Mutations in the GLRB gene was present in 4/16 (25.0%) patients and the SLC6A5 gene in 3/16 (18.8%) patients. CONCLUSION: The clinical presentation of hyperekplexia in Jordanian patients is manifested by tonic-apneic spells in all homozygous patients. The persistence of apneic spells and recurrent falls throughout childhood necessitate continuous treatment and surveillance.
[Mh] Termos MeSH primário: Hiperecplexia/genética
Hiperecplexia/fisiopatologia
[Mh] Termos MeSH secundário: Adolescente
Criança
Pré-Escolar
Consanguinidade
Erros de Diagnóstico
Epilepsia/diagnóstico
Feminino
Seguimentos
Genótipo
Proteínas da Membrana Plasmática de Transporte de Glicina/genética
Seres Humanos
Hiperecplexia/diagnóstico
Hiperecplexia/terapia
Lactente
Recém-Nascido
Jordânia
Masculino
Fenótipo
Receptores da Glicina/genética
Estudos Retrospectivos
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GLRB protein, human); 0 (Glycine Plasma Membrane Transport Proteins); 0 (Receptors, Glycine); 0 (SLC6A5 protein, human); 0 (glycine receptor alpha1)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170330
[Lr] Data última revisão:
170330
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161116
[St] Status:MEDLINE


  5 / 6 MEDLINE  
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[PMID]:27226610
[Au] Autor:Zhang Y; Bode A; Nguyen B; Keramidas A; Lynch JW
[Ad] Endereço:From the Queensland Brain Institute and.
[Ti] Título:Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia.
[So] Source:J Biol Chem;291(29):15332-41, 2016 07 15.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hyperekplexia is a rare human neuromotor disorder caused by mutations that impair the efficacy of glycinergic inhibitory neurotransmission. Loss-of-function mutations in the GLRA1 or GLRB genes, which encode the α1 and ß glycine receptor (GlyR) subunits, are the major cause. Paradoxically, gain-of-function GLRA1 mutations also cause hyperekplexia, although the mechanism is unknown. Here we identify two new gain-of-function mutations (I43F and W170S) and characterize these along with known gain-of-function mutations (Q226E, V280M, and R414H) to identify how they cause hyperekplexia. Using artificial synapses, we show that all mutations prolong the decay of inhibitory postsynaptic currents (IPSCs) and induce spontaneous GlyR activation. As these effects may deplete the chloride electrochemical gradient, hyperekplexia could potentially result from reduced glycinergic inhibitory efficacy. However, we consider this unlikely as the depleted chloride gradient should also lead to pain sensitization and to a hyperekplexia phenotype that correlates with mutation severity, neither of which is observed in patients with GLRA1 hyperekplexia mutations. We also rule out small increases in IPSC decay times (as caused by W170S and R414H) as a possible mechanism given that the clinically important drug, tropisetron, significantly increases glycinergic IPSC decay times without causing motor side effects. A recent study on cultured spinal neurons concluded that an elevated intracellular chloride concentration late during development ablates α1ß glycinergic synapses but spares GABAergic synapses. As this mechanism satisfies all our considerations, we propose it is primarily responsible for the hyperekplexia phenotype.
[Mh] Termos MeSH primário: Neurônios GABAérgicos/metabolismo
Hiperecplexia
Mutação de Sentido Incorreto
Receptores da Glicina
Sinapses
Transmissão Sináptica/genética
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Células HEK293
Seres Humanos
Hiperecplexia/genética
Hiperecplexia/metabolismo
Hiperecplexia/fisiopatologia
Ratos
Receptores da Glicina/genética
Receptores da Glicina/metabolismo
Sinapses/genética
Sinapses/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptors, Glycine); 0 (glycine receptor alpha1)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160527
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.728592


  6 / 6 MEDLINE  
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[PMID]:27028707
[Au] Autor:Wilkins ME; Caley A; Gielen MC; Harvey RJ; Smart TG
[Ad] Endereço:Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
[Ti] Título:Murine startle mutant Nmf11 affects the structural stability of the glycine receptor and increases deactivation.
[So] Source:J Physiol;594(13):3589-607, 2016 Jul 01.
[Is] ISSN:1469-7793
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:KEY POINTS: Hyperekplexia or startle disease is a serious neurological condition affecting newborn children and usually involves dysfunctional glycinergic neurotransmission. Glycine receptors (GlyRs) are major mediators of inhibition in the spinal cord and brainstem. A missense mutation, replacing asparagine (N) with lysine (K), at position 46 in the GlyR α1 subunit induced hyperekplexia following a reduction in the potency of the transmitter glycine; this resulted from a rapid deactivation of the agonist current at mutant GlyRs. These effects of N46K were rescued by mutating a juxtaposed residue, N61 on binding Loop D, suggesting these two asparagines may interact. Asparagine 46 is considered to be important for the structural stability of the subunit interface and glycine binding site, and its mutation represents a new mechanism by which GlyR dysfunction induces startle disease. ABSTRACT: Dysfunctional glycinergic inhibitory transmission underlies the debilitating neurological condition, hyperekplexia, which is characterised by exaggerated startle reflexes, muscle hypertonia and apnoea. Here we investigated the N46K missense mutation in the GlyR α1 subunit gene found in the ethylnitrosourea (ENU) murine mutant, Nmf11, which causes reduced body size, evoked tremor, seizures, muscle stiffness, and morbidity by postnatal day 21. Introducing the N46K mutation into recombinant GlyR α1 homomeric receptors, expressed in HEK cells, reduced the potencies of glycine, ß-alanine and taurine by 9-, 6- and 3-fold respectively, and that of the competitive antagonist strychnine by 15-fold. Replacing N46 with hydrophobic, charged or polar residues revealed that the amide moiety of asparagine was crucial for GlyR activation. Co-mutating N61, located on a neighbouring ß loop to N46, rescued the wild-type phenotype depending on the amino acid charge. Single-channel recording identified that burst length for the N46K mutant was reduced and fast agonist application revealed faster glycine deactivation times for the N46K mutant compared with the WT receptor. Overall, these data are consistent with N46 ensuring correct alignment of the α1 subunit interface by interaction with juxtaposed residues to preserve the structural integrity of the glycine binding site. This represents a new mechanism by which GlyR dysfunction induces startle disease.
[Mh] Termos MeSH primário: Hiperecplexia/fisiopatologia
Mutação de Sentido Incorreto
Receptores da Glicina
[Mh] Termos MeSH secundário: Desoxicorticosterona/análogos & derivados
Desoxicorticosterona/farmacologia
Glicina/farmacologia
Células HEK293
Seres Humanos
Modelos Moleculares
Picrotoxina/farmacologia
Pregnenolona/farmacologia
Receptores da Glicina/química
Receptores da Glicina/genética
Receptores da Glicina/fisiologia
Zinco/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Glycine); 0 (glycine receptor alpha1); 04Y4D91RG0 (pregnenolone sulfate); 124-87-8 (Picrotoxin); 40GP35YQ49 (Desoxycorticosterone); 4AB717DP4A (tetrahydrodeoxycorticosterone); 73R90F7MQ8 (Pregnenolone); J41CSQ7QDS (Zinc); TE7660XO1C (Glycine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160331
[St] Status:MEDLINE
[do] DOI:10.1113/JP272122



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