GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.
GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.
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DOI：
10.1002/ana.24073
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发表时间：
2014-01
影响因子：
11.2
通讯作者：
Weckhuysen, Sarah
中科院分区：
文献类型：
--
作者：
Lemke, Johannes R.;Hendrickx, Rik;Geider, Kirsten;Laube, Bodo;Schwake, Michael;Harvey, Robert J.;James, Victoria M.;Pepler, Alex;Steiner, Isabelle;Hoertnagel, Konstanze;Neidhardt, John;Ruf, Susanne;Wolff, Markus;Bartholdi, Deborah;Caraballo, Roberto;Platzer, Konrad;Suls, Arvid;De Jonghe, Peter;Biskup, Saskia;Weckhuysen, Sarah
使用面板方法鉴定新的癫痫基因，并描述突变的功能后果。使用面板的方法，我们筛选了357例患者，包括广泛的癫痫疾病的基因缺陷，已知有助于癫痫和/或智力残疾（ID）。在检测到一种新的癫痫基因突变后，我们研究了非洲爪蟾卵母细胞的功能效应，并筛选了一个后续队列。我们发现在编码N-甲基-D-天冬氨酸（NMDA）受体NR 2B亚基的GRIN 2B中，有2例West综合征和严重发育迟缓患者以及1例ID和局灶性癫痫患者发生了从头突变。患有ID和局灶性癫痫的患者在细胞外谷氨酸结合结构域（p.Arg540His）中存在错义突变，而两名West综合征患者在NR 2B离子通道形成折返环（p.Asn615Ile，p.Val618Gly）中存在错义突变。随后对47例不明原因婴儿痉挛患者进行筛查，未发现额外的新生突变，但检测到一种新型遗传性GRIN 2B剪接位点变体的携带者（c.2011-5_2011-4delTC）。突变p.Asn615Ile和p.Val618Gly导致Mg 2+阻滞显著降低和Ca 2+通透性升高，导致Ca 2+内流显著增加，而p.Arg540His导致通道功能不太严重的紊乱，对应于较温和的患者表型。我们确定GRIN 2B功能获得性突变是West综合征伴严重发育迟缓以及ID伴儿童期发作局灶性癫痫的原因。通道功能严重紊乱对应于严重的临床表型，强调了易化NMDA受体信号传导在癫痫发生中的重要作用。
To identify novel epilepsy genes using a panel approach and describe the functional consequences of mutations. Using a panel approach, we screened 357 patients comprising a vast spectrum of epileptic disorders for defects in genes known to contribute to epilepsy and/or intellectual disability (ID). After detection of mutations in a novel epilepsy gene, we investigated functional effects in Xenopus laevis oocytes and screened a follow-up cohort. We revealed de novo mutations in GRIN2B encoding the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in 2 individuals with West syndrome and severe developmental delay as well as 1 individual with ID and focal epilepsy. The patient with ID and focal epilepsy had a missense mutation in the extracellular glutamate-binding domain (p.Arg540His), whereas both West syndrome patients carried missense mutations within the NR2B ion channel-forming re-entrant loop (p.Asn615Ile, p.Val618Gly). Subsequent screening of 47 patients with unexplained infantile spasms did not reveal additional de novo mutations, but detected a carrier of a novel inherited GRIN2B splice site variant in close proximity (c.2011-5_2011-4delTC). Mutations p.Asn615Ile and p.Val618Gly cause a significantly reduced Mg2+ block and higher Ca2+ permeability, leading to a dramatically increased Ca2+ influx, whereas p.Arg540His caused less severe disturbance of channel function, corresponding to the milder patient phenotype. We identified GRIN2B gain-of-function mutations as a cause of West syndrome with severe developmental delay as well as of ID with childhood onset focal epilepsy. Severely disturbed channel function corresponded to severe clinical phenotypes, underlining the important role of facilitated NMDA receptor signaling in epileptogenesis.
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影响因子：
30.8
作者：
Carvill, Gemma L.;Regan, Brigid M.;Yendle, Simone C.;O'Roak, Brian J.;Lozovaya, Natalia;Bruneau, Nadine;Burnashev, Nail;Khan, Adiba;Cook, Joseph;Geraghty, Eileen;Sadleir, Lynette G.;Turner, Samantha J.;Tsai, Meng-Han;Webster, Richard;Ouvrier, Robert;Damiano, John A.;Berkovic, Samuel F.;Shendure, Jay;Hildebrand, Michael S.;Szepetowski, Pierre;Scheffer, Ingrid E.;Mefford, Heather C.
通讯作者：
Mefford, Heather C.
影响因子：
9.8
作者：
Kalscheuer, VM;Tao, J;Gécz, J
通讯作者：
Gécz, J
影响因子：
4.8
作者：
Madry C;Betz H;Geiger JR;Laube B
通讯作者：
Laube B
影响因子：
5.6
作者：
Berg, Anne T.;Berkovic, Samuel F.;Scheffer, Ingrid E.
通讯作者：
Scheffer, Ingrid E.
影响因子：
168.9
作者：
Rauch, Anita;Wieczorek, Dagmar;Strom, Tim M.
通讯作者：
Strom, Tim M.