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Publication Detail

Title: SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation.

Authors: Park, Julien H; Hogrebe, Max; Grüneberg, Marianne; DuChesne, Ingrid; von der Heiden, Ava L; Reunert, Janine; Schlingmann, Karl P; Boycott, Kym M; Beaulieu, Chandree L; Mhanni, Aziz A; Innes, A Micheil; Hörtnagel, Konstanze; Biskup, Saskia; Gleixner, Eva M; Kurlemann, Gerhard; Fiedler, Barbara; Omran, Heymut; Rutsch, Frank; Wada, Yoshinao; Tsiakas, Konstantinos; Santer, René; Nebert, Daniel W; Rust, Stephan; Marquardt, Thorsten

Published In Am J Hum Genet, (2015 Dec 03)

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.

PubMed ID: 26637979 Exiting the NIEHS site

MeSH Terms: Amino Acid Sequence; Carbohydrate Sequence; Cation Transport Proteins/deficiency; Cation Transport Proteins/genetics*; Cations, Divalent; Congenital Disorders of Glycosylation/blood; Congenital Disorders of Glycosylation/complications; Congenital Disorders of Glycosylation/diet therapy; Congenital Disorders of Glycosylation/genetics*; Dwarfism/blood; Dwarfism/complications; Dwarfism/diet therapy; Dwarfism/genetics*; Female; Galactose/therapeutic use; Gene Expression; High-Throughput Nucleotide Sequencing; Humans; Infant; Ion Transport; Manganese/blood*; Manganese/deficiency; Molecular Sequence Data; Mutation; Pedigree; Sequence Alignment; Spasms, Infantile/blood; Spasms, Infantile/complications; Spasms, Infantile/diet therapy; Spasms, Infantile/genetics*

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