[PDF][PDF] SLC39A8 deficiency: a disorder of manganese transport and glycosylation

JH Park, M Hogrebe, M Grüneberg, I DuChesne… - The American Journal of …, 2015 - cell.com
JH Park, M Hogrebe, M Grüneberg, I DuChesne, AL von der Heiden, J Reunert…
The American Journal of Human Genetics, 2015cell.com
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 …
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.
cell.com