Kan Anthony S H, Kusay Ali S, Mohammadi Nazanin A, Lin Susan X N, Liao Vivian W Y, Lesca Gaetan, Souci Sabrine, Milh Mathieu, Christophersen Palle, Chebib Mary, Møller Rikke S, Absalom Nathan L, Jensen Anders A, Ahring Philip K
School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, NSW 2006, Australia.
Department of Biomedical and Clinical Sciences, Linköping University, Linköping SE-581 83, Sweden.
Proc Natl Acad Sci U S A. 2024 Dec 10;121(50):e2413011121. doi: 10.1073/pnas.2413011121. Epub 2024 Dec 6.
Recent discoveries have revealed that genetic variants in γ-aminobutyric acid type A (GABA) receptor subunits can lead to both gain-of-function (GOF) and loss-of-function (LOF) receptors. GABA receptors, however, have a pseudosymmetrical pentameric assembly, and curiously diverse functional outcomes have been reported for certain homologous variants in paralogous genes (paralogous variants). To investigate this, we assembled a cohort of 11 individuals harboring paralogous M1 proline missense variants in , , and Seven mutations (α1, α1, β2, β3, β3, γ2, and γ2) in α1β2/3γ2 receptors were analyzed using electrophysiological examinations and molecular dynamics simulations. All individuals in the cohort were diagnosed with developmental and epileptic encephalopathy, with a median seizure onset age of 3.5 mo, and all exhibited global developmental delay. The clinical data for this cohort aligned with established GABA receptor GOF but not LOF cohorts. Electrophysiological assessments revealed that all variants caused GOF by increasing GABA sensitivity by 3- to 23-fold. In some cases, this was accompanied by LOF traits such as reduced maximal current amplitude and enhanced receptor desensitization. The specific subunit mutated and whether the mutation occurred in one or two subunits within the pentamer influenced the overall effects. Molecular dynamics simulations confirmed similar structural changes from all mutations, but with position-dependent asymmetry. These findings establish that paralogous variants affecting the 100% conserved proline residue in the M1 transmembrane helix of GABAR subunits all lead to overall GOF traits. The unexpected asymmetric and mixed effects on receptor function have broader implications for interpreting functional analyses for multimeric ion-channel proteins.
最近的研究发现表明，γ-氨基丁酸A型（GABA）受体亚基中的基因变异可导致功能获得性（GOF）和功能丧失性（LOF）受体。然而，GABA受体具有假对称的五聚体结构，并且对于旁系同源基因中的某些同源变异（旁系同源变异），已经报道了奇怪的不同功能结果。为了对此进行研究，我们组建了一个队列，其中包含11名在α1、α2、β2和γ2中携带旁系同源M1脯氨酸错义变异的个体。使用电生理检查和分子动力学模拟分析了α1β2/3γ2受体中的七个突变（α1、α2、β2、β3、β3、γ2和γ2）。该队列中的所有个体均被诊断为发育性和癫痫性脑病，中位癫痫发作起始年龄为3.5个月，并且均表现出全面发育迟缓。该队列的临床数据与已确立存在的GABA受体功能获得性队列相符，但与功能丧失性队列不符。电生理评估显示，所有变异均通过将GABA敏感性提高3至23倍而导致功能获得。在某些情况下，这伴随着功能丧失特征，例如最大电流幅度降低和受体脱敏增强。发生突变的特定亚基以及突变是发生在五聚体内的一个还是两个亚基中会影响总体效果。分子动力学模拟证实了所有突变都有类似的结构变化，但存在位置依赖性不对称。这些发现表明，影响GABAR亚基M1跨膜螺旋中100%保守脯氨酸残基的旁系同源变异均会导致总体功能获得特征。对受体功能产生的意外不对称和混合效应对于解释多聚体离子通道蛋白的功能分析具有更广泛的意义。
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