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De Novo Mutations in SLC 35 A 2 Encoding a UDP ‐Galactose Transporter Cause Early‐Onset Epileptic Encephalopathy
Author(s) -
Kodera Hirofumi,
Nakamura Kazuyuki,
Osaka Hitoshi,
Maegaki Yoshihiro,
Haginoya Kazuhiro,
Mizumoto Shuji,
Kato Mitsuhiro,
Okamoto Nobuhiko,
Iai Mizue,
Kondo Yukiko,
Nishiyama Kiyomi,
Tsurusaki Yoshinori,
Nakashima Mitsuko,
Miyake Noriko,
Hayasaka Kiyoshi,
Sugahara Kazuyuki,
Yuasa Isao,
Wada Yoshinao,
Matsumoto Naomichi,
Saitsu Hirotomo
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22446
Subject(s) - frameshift mutation , biology , missense mutation , genetics , mutation , mutant , mutant protein , sanger sequencing , exome sequencing , microbiology and biotechnology , gene
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 S anger sequencing in additional 328 EOEE patients identified two de novo frameshift and one missense mutations in SLC 35 A 2 at X p11.23, respectively. The three patients are all females. X ‐inactivation analysis of blood leukocyte DNA and m RNA analysis using lymphoblastoid cells derived from two patients with a frameshift mutation indicated that only the wild‐type SLC 35 A 2 allele was expressed in these cell types, at least in part likely as a consequence of skewed X ‐inactivation. SLC 35 A 2 encodes a UDP ‐galactose transporter ( UGT ), which selectively supplies UDP ‐galactose from the cytosol to the G olgi lumen. Transient expression experiments revealed that the missense mutant protein was correctly localized in the G olgi 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 SLC 35 A 2 allele and suffer from defective galactosylation, resulting in EOEE .