title: De novo mutations in SLC35A2 encoding a UDP-galactose transporter cause early-onset epileptic encephalopathy.
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.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, 236-0004, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kodera
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Maegaki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haginoya
authors.forename: Shuji
authors.initials: S
authors.lastname: Mizumoto
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.forename: Mizue
authors.initials: M
authors.lastname: Iai
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kondo
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hayasaka
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugahara
authors.forename: Isao
authors.initials: I
authors.lastname: Yuasa
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Wada
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
mesh_terms: D017668:Age of Onset; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D002648:Child; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D059472:Exome; D019066:Facies; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D021381:Protein Transport; D059368:RNA Isoforms; D013036:Spasms, Infantile / Q000175:diagnosis* / Q000235:genetics*; D000099237:UDP-Galactose Translocators
chemical_list: D009004:Monosaccharide Transport Proteins; D059368:RNA Isoforms; D000099237:UDP-Galactose Translocators
keywords: SLC35A2; congenital disorders of glycosylation; early-onset epileptic encephalopathy