Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema.
Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema.
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水通道蛋白-4和GPRC 5 B：控制脑水肿的新老玩家
DOI：
10.1093/brain/awad146
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发表时间：
2023-08-01
期刊：
影响因子：
14.5
通讯作者：
van der Knaap, Marjo S.
中科院分区：
文献类型：
--
作者：
Passchier, Emma M. J.;Kerst, Sven;Brouwers, Eelke;Hamilton, Eline M. C.;Bisseling, Quinty;Bugiani, Marianna;Waisfisz, Quinten;Kitchen, Philip;Unger, Lucas;Breur, Marjolein;Hoogterp, Leoni;de Vries, Sharon, I;Abbink, Truus E. M.;Kole, Maarten H. P.;Leurs, Rob;Vischer, Henry F.;Brignone, Maria S.;Ambrosini, Elena;Feillet, Francois;Born, Alfred P.;Epstein, Leon G.;Mansvelder, Huibert D.;Min, Rogier;van der Knaap, Marjo S.
脑水肿是多种神经系统疾病的一种危及生命的并发症。了解脑容量调节的分子机制对于治疗的发展至关重要。独特的洞察力来自以慢性脑水肿为特征的单基因疾病，其中伴有皮质下囊肿的巨脑白质脑病(MLC)是其原型。编码参与星形胶质细胞体积调节的蛋白质的MLC1或GlialCAM的变异是MLC的主要原因。在一些患者中，遗传原因尚不清楚。我们进行了遗传学研究，以确定MLC患者中新的基因变异，这些变异由临床和MRI特征诊断，没有MLC1或GlialCAM变异。我们确定了相关新蛋白在细胞和人脑组织中的亚细胞定位。我们利用细胞体积测量、生化分析和电生理学研究了新发现的变异体在体积调节通路上的功能后果。我们在两个兄弟姐妹中发现了AQP4的一个新的纯合子变体，编码水通道水通道蛋白-4，在三个无关的患者中发现了GPRC5B的两个从头开始的杂合变体，编码孤儿G蛋白偶联受体GPRC5B。AQP4突变体扰乱了膜的定位，从而破坏了通道功能。GPRC5B与MLC1、GlialCAM和Aquaporin-4一样，表达于人脑星形胶质细胞末端足部。GPRC5B患者来源的淋巴母细胞的细胞体积调节被扰乱。GPRC5B在功能上与参与星形胶质细胞体积调节的离子通道相互作用。综上所述，我们认为水通道蛋白-4和GPRC5B是遗传性脑水肿的新老参与者。我们的发现揭示了参与星形胶质细胞体积调节的蛋白质复合体，并确定GPRC5B是治疗脑水肿的新的潜在药物靶点。Passchier等人。在遗传性脑水肿患者中发现两个基因AQP4和GPRC5B的新致病变异。他们首次描述了一种与水通道蛋白-4功能障碍有关的遗传病，并将GPRC5B确定为治疗脑水肿的潜在药物靶点。有关本文的科学评论，请参见Oegema(https://doi.org/10.1093/brain/awad230)。
Brain oedema is a life-threatening complication of various neurological conditions. Understanding molecular mechanisms of brain volume regulation is critical for therapy development. Unique insight comes from monogenic diseases characterized by chronic brain oedema, of which megalencephalic leukoencephalopathy with subcortical cysts (MLC) is the prototype. Variants in MLC1 or GLIALCAM, encoding proteins involved in astrocyte volume regulation, are the main causes of MLC. In some patients, the genetic cause remains unknown. We performed genetic studies to identify novel gene variants in MLC patients, diagnosed by clinical and MRI features, without MLC1 or GLIALCAM variants. We determined subcellular localization of the related novel proteins in cells and in human brain tissue. We investigated functional consequences of the newly identified variants on volume regulation pathways using cell volume measurements, biochemical analysis and electrophysiology. We identified a novel homozygous variant in AQP4, encoding the water channel aquaporin-4, in two siblings, and two de novo heterozygous variants in GPRC5B, encoding the orphan G protein-coupled receptor GPRC5B, in three unrelated patients. The AQP4 variant disrupts membrane localization and thereby channel function. GPRC5B, like MLC1, GlialCAM and aquaporin-4, is expressed in astrocyte endfeet in human brain. Cell volume regulation is disrupted in GPRC5B patient-derived lymphoblasts. GPRC5B functionally interacts with ion channels involved in astrocyte volume regulation. In conclusion, we identify aquaporin-4 and GPRC5B as old and new players in genetic brain oedema. Our findings shed light on the protein complex involved in astrocyte volume regulation and identify GPRC5B as novel potentially druggable target for treating brain oedema. Passchier et al. identify novel pathogenic variants in two genes, AQP4 and GPRC5B, in patients with genetic brain oedema. They provide the first description of a genetic disease linked to dysfunction of the water channel aquaporin-4, and identify GPRC5B as a potentially druggable target for the treatment of brain oedema. See Oegema (https://doi.org/10.1093/brain/awad230) for a scientific commentary on this article.
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DOI：
10.1111/bpa.12602
发表时间：
2018-05
期刊：
Brain pathology (Zurich, Switzerland)
影响因子：
--
作者：
Min R;van der Knaap MS
通讯作者：
van der Knaap MS
影响因子：
5.8
作者：
Kim YJ;Greimel P;Hirabayashi Y
通讯作者：
Hirabayashi Y
影响因子：
3.3
作者：
Rash, J. E.
通讯作者：
Rash, J. E.
DOI：
10.1074/jbc.m115.646034
发表时间：
2015-07-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Kitchen P;Day RE;Taylor LH;Salman MM;Bill RM;Conner MT;Conner AC
通讯作者：
Conner AC
影响因子：
11.2
作者：
Dubey M;Brouwers E;Hamilton EMC;Stiedl O;Bugiani M;Koch H;Kole MHP;Boschert U;Wykes RC;Mansvelder HD;van der Knaap MS;Min R
通讯作者：
Min R