title: SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation.
abstract: SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably β-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders.
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
authors.forename: Julien H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Hogrebe
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Grüneberg
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: DuChesne
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
authors.forename: Ava L
authors.initials: AL
authors.lastname: von der Heiden
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Reunert
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
authors.forename: Karl P
authors.initials: KP
authors.lastname: Schlingmann
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Chandree L
authors.initials: CL
authors.lastname: Beaulieu
authors.affiliation: Genetics and Metabolism Program, Children's Hospital and the Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3A 1S1, Canada.
authors.forename: Aziz A
authors.initials: AA
authors.lastname: Mhanni
authors.affiliation: Department of Medical Genetics & Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: CeGaT GmbH, Paul-Ehrlich-Str. 23, 72076 Tübingen, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Hörtnagel
authors.affiliation: CeGaT GmbH, Paul-Ehrlich-Str. 23, 72076 Tübingen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.affiliation: CeGaT GmbH, Paul-Ehrlich-Str. 23, 72076 Tübingen, Germany.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Gleixner
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kurlemann
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fiedler
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
authors.affiliation: Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Wada
authors.affiliation: UKE, Universitätskinderklinik, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tsiakas
authors.affiliation: UKE, Universitätskinderklinik, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Santer
authors.affiliation: Department of Pediatrics & Molecular Developmental Biology, Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA; Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Rust
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany. Electronic address: thorsten.marquardt@ukmuenster.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
mesh_terms: D000595:Amino Acid Sequence; D002240:Carbohydrate Sequence; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics*; D002413:Cations, Divalent; D018981:Congenital Disorders of Glycosylation / Q000097:blood / Q000150:complications / Q000178:diet therapy / Q000235:genetics*; D004392:Dwarfism / Q000097:blood / Q000150:complications / Q000178:diet therapy / Q000235:genetics*; D005260:Female; D005690:Galactose / Q000627:therapeutic use; D015870:Gene Expression; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D017136:Ion Transport; D008345:Manganese / Q000097:blood* / Q000172:deficiency; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016415:Sequence Alignment; D013036:Spasms, Infantile / Q000097:blood / Q000150:complications / Q000178:diet therapy / Q000235:genetics*
chemical_list: D027682:Cation Transport Proteins; D002413:Cations, Divalent; C530151:SLC39A8 protein, human; D008345:Manganese; D005690:Galactose