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.

Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity

“…***P ≤ 0.001, **P ≤ 0.01, and *P ≤0. (16)(17)(18). We examined N-glycan profiles in the serum of our Slc39a8-knockout mouse models using MALDI/time-of-flight mass spectrometric (MALDI-TOF-MS) analysis ( Figure 5, A-D).…”

“…Importantly, this variant associated with lower hepatic SLC39A8 expression and reduced ZIP8 activity is associated with lower whole-blood Mn levels (1). Furthermore, SLC39A8 loss-of-function mutations were recently identified in human patients with neurological and skeletal symptoms (16)(17)(18), and these patients were found to have decreased whole-blood Mn levels and reduced protein N-glycosylation, especially galactosylation. Thus, the human data indicate that reduced expression and function of ZIP8 lead to reduced whole-blood Mn levels and protein N-glycosylation, especially galactosylation, a directionality fully consistent with our findings in Slc39a8 loss-of-function mice and rs13107325 homozygous minor allele carriers.…”

“…resulting from mutations of SLC39A8 (17,18) and TMEM165 (32) have led to protein N-glycosylation defects, especially hypogalactosylation indicative of decreased β-1,4-galactosyltransferase activity. In addition, patients with TMEM165 mutations (45) and TMEM165 knocked down cells (32) have impaired N-acetyl-glucosaminylation, another protein N-glycosylation step mediated by the Mn-dependent glycosyltransferase N-acetyl-glucosaminyltransferase II.…”

“…Mn deficiency caused by loss-of-function mutations of SLC39A8 results in CDG II and mitochondrial disease, and there is great interest in determining whether Mn supplementation is a viable treatment for patients with CDG II (17,18). Mn intoxication caused by occupational exposure (38), parenteral nutrition (30, 39), liver disease (40), and SLC30A10 mutation (26) has fl/fl and ZIP8-LSKO mice (n = 5).…”

“…Hypomorphic Slc39a8 mice exhibited diminished tissue Zn and Fe levels, stunted growth, multiple-organ hypoplasia, anemia, and perinatal death (15). Patients carrying SLC39A8 mutations had severe Mn deficiency, neurological and skeletal defects, and biomarkers of type II congenital disorders of glycosylation (CDG) (16)(17)(18), a growing family of genetic diseases that affect multiple organs and systems (19). However, there is virtually nothing known about how ZIP8 regulates metal ion metabolism in vivo.…”