De Novo Mutations in SLC35A2 Encoding a UDP‐Galactose Transporter Cause Early‐Onset Epileptic Encephalopathy |
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Authors: | Hirofumi Kodera Kazuyuki Nakamura Hitoshi Osaka Yoshihiro Maegaki Kazuhiro Haginoya Shuji Mizumoto Mitsuhiro Kato Nobuhiko Okamoto Mizue Iai Yukiko Kondo Kiyomi Nishiyama Yoshinori Tsurusaki Mitsuko Nakashima Noriko Miyake Kiyoshi Hayasaka Kazuyuki Sugahara Isao Yuasa Yoshinao Wada Naomichi Matsumoto Hirotomo Saitsu |
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Affiliation: | 1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, , Kanazawa‐ku, Yokohama, 236‐0004 Japan;2. Department of Pediatrics, Yamagata University School of Medicine, , Yamagata, 990‐9585 Japan;3. Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, , Minami‐ku, Yokohama, 232‐8555 Japan;4. Division of Child Neurology, Faculty of Medicine, Tottori University, , Yonago, 683‐8504 Japan;5. Department of Pediatrics, Tohoku University School of Medicine, , Aoba‐ku, Sendai, 980‐8574 Japan;6. Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, , Taihaku‐ku, Sendai, 982‐0241 Japan;7. Laboratory of Proteoglycan Signaling and Therapeutics, Frontier Research Center for Post‐Genomic Science and Technology, Graduate School of Life Science, Hokkaido University, , Sapporo, 001‐0021 Japan;8. Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, , Izumi, Osaka, 594‐1101 Japan;9. Division of Legal Medicine, Faculty of Medicine, Tottori University, , Yonago, 683‐8503 Japan;10. Department of Molecular Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, , Izumi, Osaka, 594‐1101 Japan |
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Abstract: | Early‐onset epileptic encephalopathies (EOEE) are severe neurological disorders characterized by frequent seizures accompanied by developmental regression or retardation. Whole‐exome sequencing of 12 patients together with five pairs of parents and subsequent Sanger sequencing in additional 328 EOEE patients identified two de novo frameshift and one missense mutations in SLC35A2 at Xp11.23, respectively. The three patients are all females. X‐inactivation analysis of blood leukocyte DNA and mRNA analysis using lymphoblastoid cells derived from two patients with a frameshift mutation indicated that only the wild‐type SLC35A2 allele was expressed in these cell types, at least in part likely as a consequence of skewed X‐inactivation. SLC35A2 encodes a UDP‐galactose transporter (UGT), which selectively supplies UDP‐galactose from the cytosol to the Golgi lumen. Transient expression experiments revealed that the missense mutant protein was correctly localized in the Golgi apparatus. In contrast, the two frameshift mutant proteins were not properly expressed, suggesting that their function is severely impaired. Defects in the UGT can cause congenital disorders of glycosylation. Of note, no abnormalities of glycosylation were observed in three serum glycoproteins, which is consistent with favorably skewed X‐inactivation. We hypothesize that a substantial number of neurons might express the mutant SLC35A2 allele and suffer from defective galactosylation, resulting in EOEE. |
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Keywords: | early‐onset epileptic encephalopathy SLC35A2 congenital disorders of glycosylation |
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