2. Academic Validation
  3. SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation

SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation

  • Am J Hum Genet. 2015 Dec 3;97(6):894-903. doi: 10.1016/j.ajhg.2015.11.003.
Julien H Park 1,  Max Hogrebe 1,  Marianne Grüneberg 1,  Ingrid DuChesne 1,  Ava L von der Heiden 1,  Janine Reunert 1,  Karl P Schlingmann 1,  Kym M Boycott 2,  Chandree L Beaulieu 2,  Aziz A Mhanni 3,  A Micheil Innes 4,  Konstanze Hörtnagel 5,  Saskia Biskup 5,  Eva M Gleixner 5,  Gerhard Kurlemann 1,  Barbara Fiedler 1,  Heymut Omran 1,  Frank Rutsch 1,  Yoshinao Wada 6,  Konstantinos Tsiakas 7,  René Santer 7,  Daniel W Nebert 8,  Stephan Rust 1,  Thorsten Marquardt 9
Affiliations

Affiliations

  • 1 Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany.
  • 2 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
  • 3 Genetics and Metabolism Program, Children's Hospital and the Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3A 1S1, Canada.
  • 4 Department of Medical Genetics & Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 5 CeGaT GmbH, Paul-Ehrlich-Str. 23, 72076 Tübingen, Germany.
  • 6 Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan.
  • 7 UKE, Universitätskinderklinik, Martinistr. 52, 20246 Hamburg, Germany.
  • 8 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.
  • 9 Universitätsklinikum Münster, Klinik und Poliklinik für Kinder- und Jugendmedizin, Albert-Schweitzer-Campus 1, Gebäude A 1, 48149 Münster, Germany. Electronic address: [email protected].
PMID: 26637979 DOI: 10.1016/j.ajhg.2015.11.003
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.

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