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Neurology Genetics
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December 2018; 4 (6) ArticleOpen Access

Brain somatic mutations in SLC35A2 cause intractable epilepsy with aberrant N-glycosylation

Nam Suk Sim, Youngsuk Seo, Jae Seok Lim, Woo Kyeong Kim, Hyeonju Son, Heung Dong Kim, Sangwoo Kim, Hyun Joo An, Hoon-Chul Kang, Se Hoon Kim, Dong-Seok Kim, Jeong Ho Lee
First published December 5, 2018, DOI: https://doi.org/10.1212/NXG.0000000000000294
Nam Suk Sim
From the 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.
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Youngsuk Seo
From the 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.
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Jae Seok Lim
From the 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.
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Woo Kyeong Kim
From the 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.
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Hyeonju Son
From the 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.
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Heung Dong Kim
From the 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.
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Sangwoo Kim
From the 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.
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Hyun Joo An
From the 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.
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Hoon-Chul Kang
From the 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.
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Se Hoon Kim
From the 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.
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Dong-Seok Kim
From the 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.
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Jeong Ho Lee
From the 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.
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Citation
Brain somatic mutations in SLC35A2 cause intractable epilepsy with aberrant N-glycosylation
Nam Suk Sim, Youngsuk Seo, Jae Seok Lim, Woo Kyeong Kim, Hyeonju Son, Heung Dong Kim, Sangwoo Kim, Hyun Joo An, Hoon-Chul Kang, Se Hoon Kim, Dong-Seok Kim, Jeong Ho Lee
Neurol Genet Dec 2018, 4 (6) e294; DOI: 10.1212/NXG.0000000000000294

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Abstract

Objective To identify whether somatic mutations in SLC35A2 alter N-glycan structures in human brain tissues and cause nonlesional focal epilepsy (NLFE) or mild malformation of cortical development (mMCD).

Methods 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.

Results Six of the 31 (19.3%) study patients exhibited brain-only mutations in SLC35A2 (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 SLC35A2 mutations.

Conclusion Our study suggests that brain somatic mutations in SLC35A2 cause intractable focal epilepsy with NLFE or mMCD via aberrant N-glycosylation in the affected brain.

Glossary

FCDII=
focal cortical dysplasia type II;
HexNAc=
N-acetyl glucosamine;
HME=
hemimegalencephaly;
mMCD=
mild malformation of cortical development;
NLFE=
nonlesional focal epilepsy;
VAF=
variant allele frequency;
WES=
whole exome sequencing

Footnotes

  • ↵* These authors contributed equally to this work.

  • Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.

  • The Article Processing Charge was funded by the authors.

  • Received July 27, 2018.
  • Accepted in final form October 3, 2018.
  • Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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