Sim Nam Suk, Seo Youngsuk, Lim Jae Seok, Kim Woo Kyeong, Son Hyeonju, Kim Heung Dong, Kim Sangwoo, An Hyun Joo, Kang Hoon-Chul, Kim Se Hoon, Kim Dong-Seok, Lee Jeong Ho
Graduate School of Medical Science and Engineering (N.S.S., J.S.L., W.K.K., J.H.L.), KAIST; Asia Glycomics Reference Site (Y.S., H.J.A.); Graduate School of Analytical Science & Technology (Y.S., H.J.A.), Chungnam National University, Daejeon, Korea; Department of Biomedical System informatics (H.S., S.K.), Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine; Division of Pediatric Neurology (H.D.K., H.C.K.), Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children's Hospital; Epilepsy Research Institute (H.D.K., H.C.K.), Yonsei University College of Medicine; Department of Pathology (S.H.K.), Yonsei University College of Medicine, Seoul, Korea; and Pediatric Neurosurgery (D.S.K.), Severance Children's Hospital, Department of Neurosurgery, Yonsei University College of Medicine, Seoul, South Korea.
Neurol Genet. 2018 Dec 5;4(6):e294. doi: 10.1212/NXG.0000000000000294. eCollection 2018 Dec.
To identify whether somatic mutations in alter N-glycan structures in human brain tissues and cause nonlesional focal epilepsy (NLFE) or mild malformation of cortical development (mMCD).
Deep whole exome and targeted sequencing analyses were conducted for matched brain and blood tissues from patients with intractable NLFE and patients with mMCD who are negative for mutations in mTOR pathway genes. Furthermore, tissue glyco-capture and nanoLC/mass spectrometry analysis were performed to examine N-glycosylation in affected brain tissue.
Six of the 31 (19.3%) study patients exhibited brain-only mutations in (mostly nonsense and splicing site mutations) encoding a uridine diphosphate (UDP)-galactose transporter. Glycome analysis revealed the presence of an aberrant N-glycan series, including high degrees of N-acetylglucosamine, in brain tissues with mutations.
Our study suggests that brain somatic mutations in cause intractable focal epilepsy with NLFE or mMCD via aberrant N-glycosylation in the affected brain.
确定编码尿苷二磷酸（UDP）-半乳糖转运蛋白的基因突变是否会改变人类脑组织中的N-聚糖结构，并导致非损伤性局灶性癫痫（NLFE）或皮质发育轻度畸形（mMCD）。
对难治性NLFE患者和mTOR通路基因突变阴性的mMCD患者的匹配脑和血组织进行深度全外显子组和靶向测序分析。此外，进行组织糖捕获和纳升液相色谱/质谱分析，以检测受影响脑组织中的N-糖基化。
31例研究患者中有6例（19.3%）在编码UDP-半乳糖转运蛋白的基因中表现出仅在脑中存在的突变（大多为无义突变和剪接位点突变）。糖组分析显示，在有该基因突变的脑组织中存在异常的N-聚糖系列，包括高度的N-乙酰葡糖胺。
我们的研究表明，该基因的脑体细胞突变通过受影响脑内异常的N-糖基化导致伴有NLFE或mMCD的难治性局灶性癫痫。
