Unit for the Diagnosis and Treatment of Congenital Metabolic Diseases, Clinical University Hospital of Santiago de Compostela, Health Research Institute of Santiago de Compostela, Santiago de Compostela, Galicia, Spain.
Centro de Investigación Biomédica de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.
Mov Disord. 2018 Jul;33(6):992-999. doi: 10.1002/mds.27315. Epub 2018 Apr 11.
Mutations in the GRIN2A gene, which encodes the GluN2A (glutamate [NMDA] receptor subunit epsilon-1) subunit of the N-methyl-d-aspartate receptor, have been identified in patients with epilepsy-aphasia spectrum disorders, idiopathic focal epilepsies with centrotemporal spikes, and epileptic encephalopathies with severe developmental delay. However, thus far, mutations in this gene have not been associated with a nonepileptic neurodevelopmental disorder with dystonia.
The objective of this study was to identify the disease-causing gene in 2 siblings with neurodevelopmental and movement disorders with no epileptiform abnormalities.
The study method was targeted next-generation sequencing panel for neuropediatric disorders and subsequent electrophysiological studies.
The 2 siblings carry a novel missense mutation in the GRIN2A gene (p.Ala643Asp) that was not detected in genomic DNA isolated from blood cells of their parents, suggesting that the mutation is the consequence of germinal mosaicism in 1 progenitor. In functional studies, the GluN2A-A643D mutation increased the potency of the agonists L-glutamate and glycine and decreased the potency of endogenous negative modulators, including protons, magnesium and zinc but reduced agonist-evoked peak current response in mammalian cells, suggesting that this mutation has a mixed effect on N-methyl-d-aspartate receptor function.
De novo GRIN2A mutations can give rise to a neurodevelopmental and movement disorder without epilepsy. © 2018 International Parkinson and Movement Disorder Society.
GRIN2A 基因突变可导致癫痫-失语症谱系障碍、特发性局灶性癫痫伴中央颞区棘波和伴有严重发育迟缓的癫痫性脑病患者出现谷氨酸 [NMDA] 受体的 GluN2A（谷氨酸 NMDA 受体亚基 epsilon-1）亚单位。然而，到目前为止，该基因突变尚未与无癫痫性神经发育障碍伴肌张力障碍相关。
本研究旨在鉴定 2 例伴有神经发育和运动障碍且无癫痫样异常的患者的致病基因。
研究方法为神经儿科疾病靶向下一代测序小组和随后的电生理研究。
这 2 名兄弟姐妹携带 GRIN2A 基因中的新型错义突变（p.Ala643Asp），该突变未在其父母血细胞基因组 DNA 中检测到，提示该突变是 1 个祖细胞生殖嵌合体的结果。在功能研究中，GluN2A-A643D 突变增加了激动剂 L-谷氨酸和甘氨酸的效力，降低了内源性负调节剂（包括质子、镁和锌）的效力，但减少了哺乳动物细胞中激动剂诱发的峰电流反应，提示该突变对 NMDA 受体功能具有混合效应。
GRIN2A 基因突变可导致无癫痫的神经发育和运动障碍。© 2018 年国际帕金森病和运动障碍学会。
