Analysis of GLRA1 in hereditary and sporadic hyperekplexia: a novel mutation in a family cosegregating for hyperekplexia and spastic paraparesis.

Elmslie, Frances; Hutchings, S M; Spencer, V; Curtis, A; Covanis, T.; Gardiner, R. M.; Rees, Michelle

doi:10.1136/jmg.33.5.435

Cited by 74 publications

(55 citation statements)

References 9 publications

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“…In glycine receptors, mutations in the M2-M3 loop can strongly inhibit channel activation, and thus cause hyperekplexia (Langosch et al, 1994;Chung et al, 2010). Our early work (Lewis et al, 1998) showed that one such hyperekplexia mutation in position 24Ј, ␣1K276E (Elmslie et al, 1996), acts by impairing gating.…”

Section: Introductionmentioning

confidence: 99%

The α1K276E Startle Disease Mutation Reveals Multiple Intermediate States in the Gating of Glycine Receptors

Lape

Plested²,

Moroni³

et al. 2012

J. Neurosci.

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Loss-of-function mutations in human glycine receptors cause hyperekplexia, a rare inherited disease associated with an exaggerated startle response. We have studied a human disease mutation in the M2-M3 loop of the glycine receptor ␣1 subunit (K276E) using direct fitting of mechanisms to single-channel recordings with the program HJCFIT. Whole-cell recordings from HEK293 cells showed the mutation reduced the receptor glycine sensitivity. In single-channel recordings, rat homomeric ␣1 K276E receptors were barely active, even at 200 mM glycine. Coexpression of the ␤ subunit partially rescued channel function. Heteromeric mutant channels opened in brief bursts at 300 M glycine (a concentration that is near-maximal for wild type) and reached a maximum one-channel open probability of about 45% at 100 mM glycine (compared to 96% for wild type). Distributions of apparent open times contained more than one component in high glycine and, therefore, could not be described by mechanisms with only one fully liganded open state. Fits to the data were much better with mechanisms in which opening can also occur from more than one fully liganded intermediate (e.g., "primed" models). Brief pulses of glycine (ϳ3 ms, 30 mM) applied to mutant channels in outside-out patches activated currents with a slower rise time (1.5 ms) than those of wild-type channels (0.2 ms) and a much faster decay. These features were predicted reasonably well by the mechanisms obtained from fitting single-channel data. Our results show that, by slowing and impairing channel gating, the K276E mutation facilitates the detection of closed reaction intermediates in the activation pathway of glycine channels.

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Section: Introductionmentioning

confidence: 99%

The α1K276E Startle Disease Mutation Reveals Multiple Intermediate States in the Gating of Glycine Receptors

Lape

Plested²,

Moroni³

et al. 2012

J. Neurosci.

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“…13 Mutations in the GLRA1 gene on chromosome 5, which codes for the alpha 1 subunit of the glycine receptor have previously been described for hyperekplexia when it occurs in isolation and also when the hyperekplexia occurs with spastic paraparesis. 14 A locus in the paracentric region of chromosome 8 was linked to 'pure' AR HSP in four out of five Tunisian families examined 15 providing evidence for genetic heterogeneity in autosomal recessive HSP. Linkage of 'pure' and 'complicated' families to the SPG1 (Xq21-22) and SPG2 (Xq28) loci on the X chromosome confirms the existence of genetic heterogeneity for X-linked HSP.…”

Section: Introductionmentioning

confidence: 99%

Linkage of AD HSP and cognitive impairment to chromosome 2p: haplotype and phenotype analysis indicates variable expression and low or delayed penetrance

et al. 1998

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We report linkage of a family affected with autosomal dominant hereditary spastic paraparesis (HSP) and/or cognitive impairment to the HSP locus on chromosome 2p. To date all families linked to this locus have been affected with 'pure' HSP. The specific pattern of cognitive impairment in this family is characterised primarily by deficits in visuo-spatial functions. We also present genetic studies that indicate variable expression and low or delayed penetrance. We have constructed a haplotype flanked by polymorphic markers D2S400 and D2S2331 that was present in 12 individuals affected with spastic paraparesis. The severity of spasticity varied markedly among these individuals. In addition four of these individuals (aged 62-70) also had a specific form of cognitive impairment. The disease haplotype was also present in an individual (age 57) who had an identical pattern of cognitive impairment as the only sign of the disease supporting the hypothesis that spastic paraparesis and cognitive impairment are the result of variable expression of a single gene (rather than a co-incidental occurrence). Haplotype reconstruction for all participating family members revealed the presence of this disease haplotype in six individuals who had normal neurological and neuropsychological examinations. All six are below the maximal age of onset in the family -60 years. This is evidence for low or late penetrance of the AD HSP gene in this family. The identification of normal individuals carrying the disease haplotype demonstrates the importance of genetic studies in combination with clinical examination when counselling at risk family members.

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“…In humans, the startle mutations R271L/Q and K276E map to the M2-M3 linker domain (5,7). At both locations, the mutations result in the substitution of a positive charged residue.…”

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confidence: 99%

Role of Charged Residues in Coupling Ligand Binding and Channel Activation in the Extracellular Domain of the Glycine Receptor

Absalom

Lewis

Kaplan

et al. 2003

Journal of Biological Chemistry

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The glycine receptor is a member of the ligand-gated ion channel receptor superfamily that mediates fast synaptic transmission in the brainstem and spinal cord. Following ligand binding, the receptor undergoes a conformational change that is conveyed to the transmembrane regions of the receptor resulting in the opening of the channel pore. Using the acetylcholine-binding protein structure as a template, we modeled the extracellular domain of the glycine receptor ␣1-subunit and identified the location of charged residues within loops 2 and 7 (the conserved Cys-loop). These loops have been postulated to interact with the M2-M3 linker region between the transmembrane domains 2 and 3 as part of the receptor activation mechanism. Charged residues were substituted with cysteine, resulting in a shift in the concentration-response curves to the right in each case. Covalent modification with 2-(trimethylammonium) ethyl methanethiosulfonate was demonstrated only for K143C, which was more accessible in the open state than the closed state, and resulted in a shift in the EC 50 toward wild-type values. Charge reversal mutations (E53K, D57K, and D148K) also impaired channel activation, as inferred from increases in EC 50 values and the conversion of taurine from an agonist to an antagonist in E53K and D57K. Thus, each of the residues Glu-53, Asp-57, Lys-143, and Asp-148 are implicated in channel gating. However, the double reverse charge mutations E53K:K276E, D57K:K276E, and D148K:K276E did not restore glycine receptor function. These results indicate that loops 2 and 7 in the extracellular domain play an important role in the mechanism of activation of the glycine receptor although not by a direct electrostatic mechanism.Fast synaptic transmission in the central nervous system is mediated by members of the ligand-gated ion channel (LGIC) 1 receptor superfamily. The glycine receptor (GlyR) is a member of the nicotinic-like LGIC superfamily that includes the nicotinic acetylcholine (nAChR), serotonin type 3 (5-HT 3 R), and ␥-aminobutyric acid (GABA A R) receptors (1, 2). Each of these receptors are pentameric complexes arranged around a central ion conducting pore. Individual subunits share a similar membrane topology, with hydropathy analysis predicting a large extracellular domain at the N terminus and four putative transmembrane domains (M1-M4) (1). A key characteristic of these receptors is the integral ion channel that is opened following ligand binding. The extracellular domain contains the ligand binding site, which is spatially separate from the M2 domain that lines the ion channel pore of these receptors (3, 4). While there is an accumulated body of data on the structures involved in ligand binding (2) and the ion channel pore (2-4), relatively little is known about the structures that may link these two spatially separate domains to effect receptor activation.Inherited mutations located in the regions flanking the M2 domain of the GlyR ␣1-subunit are associated with human startle disease (hyperekplexia) (5) and start...

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Analysis of GLRA1 in hereditary and sporadic hyperekplexia: a novel mutation in a family cosegregating for hyperekplexia and spastic paraparesis.

Cited by 74 publications

References 9 publications

The α1K276E Startle Disease Mutation Reveals Multiple Intermediate States in the Gating of Glycine Receptors

The α1K276E Startle Disease Mutation Reveals Multiple Intermediate States in the Gating of Glycine Receptors

Linkage of AD HSP and cognitive impairment to chromosome 2p: haplotype and phenotype analysis indicates variable expression and low or delayed penetrance

Role of Charged Residues in Coupling Ligand Binding and Channel Activation in the Extracellular Domain of the Glycine Receptor

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