A novel GLRA1 mutation in a recessive hyperekplexia pedigree

Forsyth, Rob; Gika, Artemis; Ginjaar, Ieke B.; Tijssen, Marina A. J.

doi:10.1002/mds.21574

Cited by 14 publications

(6 citation statements)

References 13 publications

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“…There appears to be three clusters of cases: first, Caucasian cases predominate (38%) 12. This can be partially explained by referral bias due to the proximity of local tertiary testing centres, and a healthcare setting that facilitates diagnosis and referral for testing.…”

Section: Discussionmentioning

confidence: 99%

Ethnicity can predict GLRA1 genotypes in hyperekplexia

Thomas

Drew

Wood

et al. 2014

Journal of Neurology, Neurosurgery & Psychiatry

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Section: Discussionmentioning

confidence: 99%

Ethnicity can predict GLRA1 genotypes in hyperekplexia

Thomas

Drew

Wood

et al. 2014

Journal of Neurology, Neurosurgery & Psychiatry

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“…The mode of inheritance was autosomal dominant. HPX has been identified in >100 pedigrees and in >120 sporadic cases (Bakker et al., 2006; Siren et al., 2006; Doria et al., 2007; Forsyth et al., 2007; Masri & Hamamy, 2007; Gregory et al., 2008; Al‐Owain et al., 2011; Zoons et al., 2012). There are three clinical symptoms: generalized stiffness at birth, excessive startle reflexes, and generalized stiffness following startle.…”

Section: Hyperekplexiamentioning

confidence: 99%

The startle syndromes: Physiology and treatment

Dreissen

Tijssen

2012

Epilepsia

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SUMMARYStartle syndromes are paroxysmal and show stimulus sensitivity, placing them in the differential diagnosis of epileptic seizures. Startle syndromes form a heterogeneous group of disorders with three categories: hyperekplexia (HPX), stimulus-induced disorders, and neuropsychiatric syndromes. HPX is characterized by an exaggerated motor startle reflex combined with stiffness and is caused by mutations in different parts of the inhibitory glycine receptor, leading to brainstem pathology. The preserved consciousness distinguishes it from epileptic seizures. Clonazepam is the first-choice therapy. The stimulusinduced disorders cover a broad range of epileptic and nonepileptic disorders, and distinguishing the two can be difficult. Additional information from electroencephalography (EEG) and video registration can help. Many stimulus-induced disorders now have an identified gene defect. Antiepileptic drugs, including benzodiazepines, are frequently mentioned as the best treatment option. Neuropsychiatric syndromes are on the borderland of neurology and psychiatry, and their etiology is poorly understood. These syndromes include startle-induced tics, culture-specific disorders such as Latah, and functional startle syndromes. The electromyography (EMG) startle reflex in these syndromes is characterized by variable recruitment patterns and the presence of a second ''orienting'' response. Treatment options are limited, but urgently required. In the clinical setting, the patient's history and a (home) video recording together with genetic and electrophysiologic testing help to classify these challenging disorders.

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“…Thus, although functional evidence for cholesterol contacts in GlyRs is limited, specific state-dependent interactions identified in this work are consistent with an influential region of channel function. Peripheral to these direct cholesterol contacts, several of the residues (Gln-242, Tyr-244, Trp-255, Ala-267) we identify (Table ) as relevant for allosteric gating have also been linked to hyperekplexia ,,− (Figure b). Substituting Glu at the M1 residue Gln-242 produces leaky channels, possibly due to an enhanced interaction with the M2 residue Arg-287 described above. , Conversely, substituting Glu at the M2 residue Ala-267 in the inner mouth of the pore suppresses recovery from desensitization .…”

Section: Discussionmentioning

confidence: 99%

Allosteric Cholesterol Site in Glycine Receptors Characterized through Molecular Simulations

Jalalypour,

Howard,

Lindahl

2024

J. Phys. Chem. B

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Glycine receptors are pentameric ligand-gated ion channels that conduct chloride ions across postsynaptic membranes to facilitate fast inhibitory neurotransmission. In addition to gating by the glycine agonist, interactions with lipids and other compounds in the surrounding membrane environment modulate their function, but molecular details of these interactions remain unclear, in particular, for cholesterol. Here, we report coarse-grained simulations in a model neuronal membrane for three zebrafish glycine receptor structures representing apparent resting, open, and desensitized states. We then converted the systems to all-atom models to examine detailed lipid interactions. Cholesterol bound to the receptor at an outer-leaflet intersubunit site, with a preference for the open and desensitized versus resting states, indicating that it can bias receptor function. Finally, we used short atomistic simulations and iterative amino acid perturbations to identify residues that may mediate allosteric gating transitions. Frequent cholesterol contacts in atomistic simulations clustered with residues identified by perturbation analysis and overlapped with mutations influencing channel function and pathology. Cholesterol binding at this site was also observed in a recently reported pig heteromeric glycine receptor. These results indicate state-dependent lipid interactions relevant to allosteric transitions of glycine receptors, including specific amino acid contacts applicable to biophysical modeling and pharmaceutical design.

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A novel GLRA1 mutation in a recessive hyperekplexia pedigree

Abstract: We report the identification of a novel Y228C mutation within the M1 trans-membrane domain of the GLRA1 subunit of the glycine receptor responsible for a severe recessive hyperekplexia phenotype in a Kurdish pedigree.

Cited by 14 publications

References 13 publications

Ethnicity can predict GLRA1 genotypes in hyperekplexia

Ethnicity can predict GLRA1 genotypes in hyperekplexia

The startle syndromes: Physiology and treatment

Allosteric Cholesterol Site in Glycine Receptors Characterized through Molecular Simulations

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