{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T20:43:37Z","timestamp":1775940217916,"version":"3.50.1"},"posted":{"date-parts":[[2025,3,11]]},"group-title":"Cell Biology","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T00:00:00Z","timestamp":1741651200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Gamma-aminobutyric acid type A receptors (GABA\n                  <jats:sub>A<\/jats:sub>\n                  Rs) are the major inhibitory neurotransmitter-gated channel in the mammalian central nervous system. GABA\n                  <jats:sub>A<\/jats:sub>\n                  Rs function as heteropentamers, typically composed of two \u03b11, two \u03b22, and one \u03b32 subunits. Protein homeostasis between GABA\n                  <jats:sub>A<\/jats:sub>\n                  R folding, trafficking, assembly, and degradation is critical to ensure normal physiological functions. Variants in genes encoded for GABA\n                  <jats:sub>A<\/jats:sub>\n                  Rs lead to numerous neurological disorders, such as genetic epilepsy with or without neurodevelopmental delay. While these variants are associated with severe clinical presentations of epilepsy, the molecular mechanisms driving the disease remain to be elucidated. In this study, we focused on four missense epilepsy-associated variants (EAVs) in the\n                  <jats:italic>GABRB2<\/jats:italic>\n                  gene: Q209F210delinsH (c. 627_629del), R240T (c. 719G&gt;C), I246T (c. 737T&gt;C), and I299S (c. 896T&gt;G). HEK293T cells exogenously expressing these \u03b22 variants exhibited significantly reduced GABA-induced peak chloride current, indicating their loss of function. However, the four \u03b22 EAVs differed in the degree of proteostasis deficiencies, including increased ER retention, compromised assembly, decreased protein stability, and reduced trafficking and surface expression, with Q209F210delinsH and R240T variants leading to the most severe degradation. Collectively, these results indicate that these epilepsy-linked variants have debilitating effects on the early biogenesis of the \u03b22 subunit, causing misfolding, aggregation, and rapid degradation before it can be assembled with other subunits and transported to the plasma membrane. Overall, our work offers crucial mechanistic insight into how specific \u03b22 missense variants impact the proteostasis maintenance of GABA\n                  <jats:sub>A<\/jats:sub>\n                  Rs, which could facilitate the development of effective therapeutics for genetic epilepsy by targeting trafficking-deficient GABA\n                  <jats:sub>A<\/jats:sub>\n                  R variants.\n                <\/jats:p>","DOI":"10.1101\/2025.03.09.642292","type":"posted-content","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T11:02:07Z","timestamp":1741690927000},"source":"Crossref","is-referenced-by-count":0,"title":["Missense variants in GABA\n                  <sub>A<\/sub>\n                  receptor beta2 subunit disrupt receptor biogenesis and cause loss of function"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2171-3141","authenticated-orcid":false,"given":"Xi","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3284-9012","authenticated-orcid":false,"given":"Ya-Juan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6419-9296","authenticated-orcid":false,"given":"Ting-Wei","family":"Mu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041112561452000_2025.03.09.642292v1.1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R112.386664"},{"key":"2026041112561452000_2025.03.09.642292v1.2","doi-asserted-by":"publisher","DOI":"10.1042\/bst0320529"},{"key":"2026041112561452000_2025.03.09.642292v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/nature13293"},{"key":"2026041112561452000_2025.03.09.642292v1.4","doi-asserted-by":"publisher","DOI":"10.1177\/08830738030180012101"},{"key":"2026041112561452000_2025.03.09.642292v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/bs.apcsb.2015.11.002"},{"key":"2026041112561452000_2025.03.09.642292v1.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2004.02481.x"},{"key":"2026041112561452000_2025.03.09.642292v1.7","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3355-04.2004"},{"key":"2026041112561452000_2025.03.09.642292v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2370"},{"key":"2026041112561452000_2025.03.09.642292v1.9","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22536"},{"key":"2026041112561452000_2025.03.09.642292v1.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.705004"},{"key":"2026041112561452000_2025.03.09.642292v1.11","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00313"},{"key":"2026041112561452000_2025.03.09.642292v1.12","doi-asserted-by":"publisher","DOI":"10.1002\/path.2697"},{"key":"2026041112561452000_2025.03.09.642292v1.13","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.684526"},{"key":"2026041112561452000_2025.03.09.642292v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.02.018"},{"key":"2026041112561452000_2025.03.09.642292v1.15","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00038.2021"},{"key":"2026041112561452000_2025.03.09.642292v1.16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1424958112"},{"key":"2026041112561452000_2025.03.09.642292v1.17","doi-asserted-by":"publisher","DOI":"10.36255\/exon-publications-epilepsy-gaba-receptor"},{"key":"2026041112561452000_2025.03.09.642292v1.18","doi-asserted-by":"crossref","unstructured":"D.Y. 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