The novel hyperekplexia allele GLRA1(S267N) affects the ethanol site of the glycine receptor

Becker, Karsten; Breitinger, Hans‐Georg; Humeny, Andreas; Meinck, Hans‐Michael; Dietz, Bernd; Aksu, Fuat; Becker, Cord‐Michael

doi:10.1038/sj.ejhg.5201958

Cited by 16 publications

(19 citation statements)

References 18 publications

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“…Several in vitro studies led to the identification of distinct residues involved in ethanol potentiation (Mihic et al, 1997). S267N located in the ion channel pore is one of the key residues for ethanol modulation and has also been found in patients that suffer from hyperekplexia (Becker et al, 2008). This mutant displayed differences in agonist potency as well as ethanol modulation and demonstrated that a disease-associated Glra1 mutation harbors the ability to alter drug responses.…”

Section: Knock-in Mouse Mutantsmentioning

confidence: 99%

“…In hyperekplexia, affected neonates exhibit exaggerated startle responses and muscle stiffness following an unexpected acoustic noise or a tactile stimulus, which may result in fatal apnea. During early childhood the muscle tone returns to normal levels, but startling persists into the adulthood (Andermann et al, 1980; Shiang et al, 1993; Becker et al, 2008). Predominantly, single point mutations in the GLRA1 gene encoding the GlyR subunit α1 (GlyRα1) underlie the pathology in humans.…”

Section: Introductionmentioning

confidence: 99%

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Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?

Schaefer

Vogel

Villmann

2012

Front. Mol. Neurosci.

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Defects in glycinergic inhibition result in a complex neuromotor disorder in humans known as hyperekplexia (OMIM 149400) with similar phenotypes in rodents characterized by an exaggerated startle reflex and hypertonia. Analogous to genetic defects in humans single point mutations, microdeletions, or insertions in the Glra1 gene but also in the Glrb gene underlie the pathology in mice. The mutations either localized in the α (spasmodic, oscillator, cincinnati, Nmf11) or the β (spastic) subunit of the glycine receptor (GlyR) are much less tolerated in mice than in humans, leaving the question for the existence of different regulatory elements of the pathomechanisms in humans and rodents. In addition to the spontaneous mutations, new insights into understanding of the regulatory pathways in hyperekplexia or glycine encephalopathy arose from the constantly increasing number of knock-out as well as knock-in mutants of GlyRs. Over the last five years, various efforts using in vivo whole cell recordings provided a detailed analysis of the kinetic parameters underlying glycinergic dysfunction. Presynaptic compensation as well as postsynaptic compensatory mechanisms in these mice by other GlyR subunits or GABAA receptors, and the role of extra-synaptic GlyRs is still a matter of debate. A recent study on the mouse mutant oscillator displayed a novel aspect for compensation of functionality by complementation of receptor domains that fold independently. This review focuses on defects in glycinergic neurotransmission in mice discussed with the background of human hyperekplexia en route to strategies of compensation.

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Section: Knock-in Mouse Mutantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?

Schaefer

Vogel

Villmann

2012

Front. Mol. Neurosci.

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“…at ASPET Journals on May 9, 2018 jpet.aspetjournals.org cine-and taurine-induced displacement of strychnine binding, without changes in the strychnine binding per se, all have been observed in other mutations that cause deficits in the glycinergic transmission (Saul et al, 1994;Rajendra et al, 1995;Moorhouse et al, 1999;Castaldo et al, 2004;Becker et al, 2008).…”

mentioning

confidence: 95%

Characterization of Two Mutations, M287L and Q266I, in the α1 Glycine Receptor Subunit That Modify Sensitivity to Alcohols

Borghese

Blednov

et al. 2011

J Pharmacol Exp Ther

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Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels. Ethanol potentiates glycine activation of the GlyR, and putative binding sites for alcohol are located in the transmembrane (TM) domains between and within subunits. To alter alcohol sensitivity of GlyR, we introduced two mutations in the GlyR ␣1 subunit, M287L (TM3) and Q266I (TM2). After expression in Xenopus laevis oocytes, both mutants showed a reduction in glycine sensitivity and glycine-induced maximal currents. Activation by taurine, another endogenous agonist, was almost abolished in the M287L GlyR. The ethanol potentiation of glycine currents was reduced in the M287L GlyR and eliminated in Q266I. Physiological levels of zinc (100 nM) potentiate glycine responses in wild-type GlyR and also enhance the ethanol potentiation of glycine responses. Although zinc potentiation of glycine responses was unchanged in both mutants, zinc enhancement of ethanol potentiation of glycine responses was absent in M287L GlyRs. The Q266I mutation decreased conductance but increased mean open time (effects not seen in M287L). Two lines of knockin mice bearing these mutations were developed. Survival of homozygous knockin mice was impaired, probably as a consequence of impaired glycinergic transmission. Glycine showed a decreased capacity for displacing strychnine binding in heterozygous knockin mice. Electrophysiology in isolated neurons of brain stem showed decreased glycine-mediated currents and decreased ethanol potentiation in homozygous knockin mice. Molecular models of the wildtype and mutant GlyRs show a smaller water-filled cavity within the TM domains of the Q266I ␣1 subunit. The behavioral characterization of these knockin mice is presented in a companion article (J Pharmacol Exp Ther 340:317-329, 2012).

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“…The disorder is associated with mutations of the GLRA1 gene (Rees et al, 1994;Becker et al, 2006Becker et al, , 2008, the ␤ subunit gene GLRB , and the gene encoding the glycine transporter GlyT2 (Eulenburg et al, 2006;Rees et al, 2006). The mouse mutants oscillator (Glra1 spd-ot ) Kling et al, 1997) and spasmodic (Glra1 spd ) (Ryan et al, 1994;Saul et al, 1994) carry orthologous mutations in the Glra1 gene, whereas the spastic (Glrb spa ) mouse carries a ␤ subunit mutation (Becker et al, 1992;Kingsmore et al, 1994;Mülhardt et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Functional Complementation ofGlra1^spd-ot, a Glycine Receptor Subunit Mutant, by Independently Expressed C-Terminal Domains

Villmann¹,

Oertel²,

Ma-Högemeier³

et al. 2009

J. Neurosci.

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The oscillator mouse (Glra1 spd-ot ) carries a 9 bp microdeletion plus a 2 bp microinsertion in the glycine receptor ␣1 subunit gene, resulting in the absence of functional ␣1 polypeptides from the CNS and lethality 3 weeks after birth. Depending on differential use of two splice acceptor sites in exon 9 of the Glra1 gene, the mutant allele encodes either a truncated ␣1 subunit (spd ot -trc) or a polypeptide with a C-terminal missense sequence (spd ot -elg). During recombinant expression, both splice variants fail to form ion channels. In complementation studies, a tail construct, encoding the deleted C-terminal sequence, was coexpressed with both mutants. Coexpression with spd ot -trc produced glycine-gated ion channels. Rescue efficiency was increased by inclusion of the wild-type motif RRKRRH. In cultured spinal cord neurons from oscillator homozygotes, viral infection with recombinant C-terminal tail constructs resulted in appearance of endogenous ␣1 antigen. The functional rescue of ␣1 mutants by the C-terminal tail polypeptides argues for a modular subunit architecture of members of the Cys-loop receptor family.

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The novel hyperekplexia allele GLRA1(S267N) affects the ethanol site of the glycine receptor

Cited by 16 publications

References 18 publications

Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?

Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?

Characterization of Two Mutations, M287L and Q266I, in the α1 Glycine Receptor Subunit That Modify Sensitivity to Alcohols

Functional Complementation ofGlra1^spd-ot, a Glycine Receptor Subunit Mutant, by Independently Expressed C-Terminal Domains

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The novel hyperekplexia allele GLRA1(S267N) affects the ethanol site of the glycine receptor

Cited by 16 publications

References 18 publications

Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?

Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?

Characterization of Two Mutations, M287L and Q266I, in the α1 Glycine Receptor Subunit That Modify Sensitivity to Alcohols

Functional Complementation ofGlra1spd-ot, a Glycine Receptor Subunit Mutant, by Independently Expressed C-Terminal Domains

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Functional Complementation ofGlra1^spd-ot, a Glycine Receptor Subunit Mutant, by Independently Expressed C-Terminal Domains