Clinical, genetic, and functional characterization of the glycine receptor β-subunit A455P variant in a family affected by hyperekplexia syndrome

Ghada I. Aboheimed; Maha M. AlRasheed; Sultan Almudimeegh; Karla A. Peña-Guerra; Kelly J. Cardona-Londoño; Mustafa A. Salih; Mohammed Z. Seidahmed; Futwan Al-Mohanna; Dilek Colak; Robert J Harvey; Kirsten Harvey; Stefan T. Arold; Namik Kaya; Arnaud J. Ruiz

doi:10.1016/j.jbc.2022.102018

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Clinical, genetic, and functional characterization of the glycine receptor β-subunit A455P variant in a family affected by hyperekplexia syndrome

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Clinical, genetic, and functional characterization of the glycine receptor β-subunit A455P variant in a family affected by hyperekplexia syndrome

Ghada I. Aboheimed, Maha M. AlRasheed, Sultan Almudimeegh, Karla A. Peña-Guerra, Kelly J. Cardona-Londoño, Mustafa A. Salih, Mohammed Z. Seidahmed, Futwan Al-Mohanna, Dilek Colak, Robert J Harvey, …

Journal of Biological Chemistry, Vol.298(7), pp.1-12

2022

DOI: https://doi.org/10.1016/j.jbc.2022.102018

PMCID: PMC9241032

PMID: 35526563

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Abstract

autozygosity mapping

coimmunoprecipitation

confocal imaging

exome sequencing

GLRB

immunohistochemistry

patch clamp

startle disease

Hyperekplexia is a rare neurological disorder characterized by exaggerated startle responses affecting newborns with the hallmark characteristics of hypertonia, apnea, and noise or touch-induced nonepileptic seizures. The genetic causes of the disease can vary, and several associated genes and mutations have been reported to affect glycine receptors (GlyRs); however, the mechanistic links between GlyRs and hyperekplexia are not yet understood. Here, we describe a patient with hyperekplexia from a consanguineous family. Extensive genetic screening using exome sequencing coupled with autozygome analysis and iterative filtering supplemented by in silico prediction identified that the patient carries the homozygous missense mutation A455P in GLRB, which encodes the GlyR β-subunit. To unravel the physiological and molecular effects of A455P on GlyRs, we used electrophysiology in a heterologous system as well as immunocytochemistry, confocal microscopy, and cellular biochemistry. We found a reduction in glycine-evoked currents in N2A cells expressing the mutation compared to WT cells. Western blot analysis also revealed a reduced amount of GlyR β protein both in cell lysates and isolated membrane fractions. In line with the above observations, coimmunoprecipitation assays suggested that the GlyR α1-subunit retained coassembly with βA455P to form membrane-bound heteromeric receptors. Finally, structural modeling showed that the A455P mutation affected the interaction between the GlyR β-subunit transmembrane domain 4 and the other helices of the subunit. Taken together, our study identifies and validates a novel loss-of-function mutation in GlyRs whose pathogenicity is likely to cause hyperekplexia in affected individuals.

Details

Title: Clinical, genetic, and functional characterization of the glycine receptor β-subunit A455P variant in a family affected by hyperekplexia syndrome
Authors: Ghada I. Aboheimed (Author) - King Faisal Specialist Hospital & Research Centre
Maha M. AlRasheed (Author) - King Saud University
Sultan Almudimeegh (Author) - King Saud University
Karla A. Peña-Guerra (Author) - King Abdullah University of Science and Technology
Kelly J. Cardona-Londoño (Author) - King Abdullah University of Science and Technology
Mustafa A. Salih (Author) - King Saud University
Mohammed Z. Seidahmed (Author) - Security Forces Hospital
Futwan Al-Mohanna (Author) - King Faisal Specialist Hospital & Research Centre
Dilek Colak (Author) - Department of Biostatistics and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia
Robert J Harvey (Author) - Department of Pharmacology, The School of Pharmacy, University College London, London, United Kingdom
Kirsten Harvey (Author) - University College London
Stefan T. Arold (Author) - Université de Montpellier
Namik Kaya (Author) - King Faisal Specialist Hospital & Research Centre
Arnaud J. Ruiz (Author) - University College London
Publication details: Journal of Biological Chemistry, Vol.298(7), pp.1-12
Publisher: Elsevier Inc.
Date published: 2022
DOI: 10.1016/j.jbc.2022.102018
ISSN: 1083-351X
PMID: 35526563; PMC9241032
Copyright note: Copyright (c) 2022 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Organisation Unit: School of Health; University of the Sunshine Coast, Queensland; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99655797602621
Output Type: Journal article

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