SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation

• Published in: American journal of human genetics Vol. 97; no. 6; pp. 894 - 903
• Main 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.12.2015; Cell Press; Elsevier
• Subjects: Amino Acid Sequence; Biosynthesis; Carbohydrate Sequence; Cation Transport Proteins - deficiency; Cation Transport Proteins - genetics; Cations, Divalent; Congenital diseases; Congenital Disorders of Glycosylation - blood; Congenital Disorders of Glycosylation - complications; Congenital Disorders of Glycosylation - diet therapy; Congenital Disorders of Glycosylation - genetics; Dwarfism; Dwarfism - blood; Dwarfism - complications; Dwarfism - diet therapy; Dwarfism - genetics; Enzymes; Female; Galactose - therapeutic use; Gene Expression; Glycoproteins; Glycosylation; 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
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2015.11.003

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.