Aboheimed, Ghada I;
AlRasheed, Maha M;
Almudimeegh, Sultan;
Peña-Guerra, Karla A;
Cardona-Londoño, Kelly J;
Salih, Mustafa A;
Seidahmed, Mohammed Z;
... Ruiz, Arnaud J; + view all
(2022)
Clinical, genetic, and functional characterization of the glycine receptor β-subunit A455P variant in a family affected by hyperekplexia syndrome.
Journal of Biological Chemistry
, Article 102018. 10.1016/j.jbc.2022.102018.
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Abstract
Hyperekplexia is a rare neurological disorder characterized by exaggerated startle response affecting newborns with the hallmark characteristics of hypertonia, apnea, and noise or touch-induced non-epileptic 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 wild type 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, co-immunoprecipitation assays suggested that the GlyR α1-subunit retained co-assembly with βA455P to form membrane-bound heteromeric receptors. Finally, structural modelling 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.
| Type: | Article |
|---|---|
| Title: | Clinical, genetic, and functional characterization of the glycine receptor β-subunit A455P variant in a family affected by hyperekplexia syndrome |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jbc.2022.102018 |
| Publisher version: | https://doi.org/10.1016/j.jbc.2022.102018 |
| Language: | English |
| Additional information: | © 2022 Published by Elsevier Ltd. This is an open access article under the CC BY 4.0 license Attribution 4.0 International (https://creativecommons.org/licenses/by/4.0/) |
| Keywords: | Autozygosity mapping, GLRB, co-immunoprecipitation, confocal imaging, exome sequencing, immunohistochemistry, patch clamp, startle disease |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10148715 |
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