Mixed functional consequences of the N651D GRIA3 variant: a case of early-onset developmental and epileptic encephalopathy with parkinsonism.

IF 3.7 2区 医学 Q2 GENETICS & HEREDITY
Carmen Fons, Yu-Han Ge, Laura Kristine Rasmussen, Yun Stone Shi, Allan Bayat
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引用次数: 0

Abstract

Rare variants in GRIA3, the gene encoding the GluA3 subunit of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs), are associated with defects in early brain development. Disease-causing variants are generally categorised as either loss of function (LoF) or gain of function (GoF) that appear to be linked to different symptoms. Here, we reported a de novo variant (N651D) that has mixed LoF and GoF in a female patient with a devastating developmental and epileptic encephalopathy, parkinsonism and cortical malformation. N651D is located in the M3 segment, which forms the filter pore of AMPAR tetramers. Interestingly, functional assays revealed that glutamate induced no currents in GluA3_N651D homomeric receptors, likely indicating an LoF effect. However, when co-expressed with the GluA2 subunit, the GluA2/A3_N651D heteromeric receptors showed slower deactivation and desensitisation curves, along with elevated non-desensitising steady-state currents, features typically observed in GoF variants. We speculate that variants with mixed LoF and GoF effects may lead to a more devastating phenotype compared with variants with GoF effects only.

N651D GRIA3变异的混合功能后果:早发性发育性和癫痫性脑病伴帕金森病1例
编码氨基-3-羟基-5-甲基-4-异恶唑丙酸(AMPA)型谷氨酸受体(AMPARs) GluA3亚基的基因GRIA3的罕见变异与早期大脑发育缺陷有关。致病变异通常分为功能丧失(LoF)或功能获得(GoF),它们似乎与不同的症状有关。在这里,我们报道了一名患有破坏性发育性和癫痫性脑病、帕金森病和皮质畸形的女性患者的LoF和GoF混合的新生变异(N651D)。N651D位于M3段,形成AMPAR四聚体的过滤孔。有趣的是,功能分析显示谷氨酸在GluA3_N651D同质受体中没有诱导电流,可能表明LoF效应。然而,当与GluA2亚基共表达时,GluA2/A3_N651D异质受体表现出较慢的失活和脱敏曲线,以及升高的非脱敏稳态电流,这些特征通常在GoF变异体中观察到。我们推测,与仅具有GoF效应的变异相比,具有混合LoF和GoF效应的变异可能导致更具破坏性的表型。
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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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