Alternative titles; symbols
HGNC Approved Gene Symbol: SLC39A8
SNOMEDCT: 1187171005;
Cytogenetic location: 4q24 Genomic coordinates (GRCh38) : 4:102,251,041-102,345,482 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q24 | Congenital disorder of glycosylation, type IIn | 616721 | Autosomal recessive | 3 |
The SLC39A8 gene encodes a transmembrane protein that acts as a transporter of several divalent cations, including manganese (Mn), zinc (Zn), cadmium (Cd), and iron (Fe), across the plasma membrane (summary by Boycott et al., 2015 and Park et al., 2015).
By subtractive hybridization to identify genes upregulated in monocytes stimulated with Mycobacterium bovis BCG cell wall, followed by database analysis and 5-prime and 3-prime RACE, Begum et al. (2002) cloned SLC39A8, which they designated BIGM103. Northern blot analysis detected a 3.4-kb transcript expressed in several human tissues and cell lines, with highest expression in pancreas. EST database analysis indicated that there are 5-prime splice variants of SLC39A8. SLC39A8 also has 3 putative start sites in 2 frames. The longest deduced protein contains 460 amino acids and has a calculated molecular mass of about 49.6 kD. SLC39A8 has 7 putative transmembrane (TM) domains, a potential signal cleavage site, a perfect leucine zipper motif, a metalloprotease motif, and 11 cysteine residues mainly clustered at the N-terminal hydrophilic region and within the extra membrane loop between TM3 and TM4. SLC39A8 also contains 3 N-glycosylation sites and 3 putative phosphorylation sites. The major SLC39A8 transcript was associated with the lysosomal/endosomal compartment following transfection of several human and simian cell lines. Proteins transcribed from alternate reading frames showed either nuclear localization or both cytoplasmic and nuclear localization. Western blot analysis of a monocytic leukemia cell line detected proteins of about 90, 52, and 42 kD. Detergent extraction confirmed that the major 52-kD species is an integral membrane protein.
By searching databases for sequences similar to a unique motif within LIV1 (SLC39A6; 608731), Taylor and Nicholson (2003) identified SLC39A8, which they designated LZT-Hs6. The deduced 460-amino acid protein contains a long N terminus, followed by 8 putative TM domains and a short C terminus. It also has a high histidine content, including a motif similar to the catalytic zinc-binding site of matrix metalloproteases.
Begum et al. (2002) found that monocyte SLC39A8 was induced by live and heat-killed Mycobacterium bovis bacterial cell wall and inflammatory cytokines like TNFA (191160). Basal expression of the major 52-kD SLC39A8 isoform in a monocytic leukemia cell line was downregulated following phorbol ester treatment. Using a zinc-specific fluorescent probe, Begum et al. (2002) demonstrated that SLC39A8 increased intracellular zinc ion accumulation and retention in transfected Chinese hamster ovary cells.
Begum et al. (2002) determined that the SLC39A8 gene contains at least 8 exons and spans about 84 kb.
By genomic sequence analysis, Begum et al. (2002) mapped the SLC39A8 gene to chromosome 4q22-q24.
Congenital Disorder of Glycosylation Type IIn
In 6 patients of Hutterite descent and in 2 sibs, born of consanguineous Egyptian parents, with congenital disorder of glycosylation type IIn (CDG2N; 616721), Boycott et al. (2015) identified the same homozygous missense mutation in the SLC39A8 gene (G38R; 608732.0001). The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the families. Haplotype analysis did not suggest a founder effect between the Hutterite and Egyptian patients. Patient cells showed normal localization of the mutant protein, but blood levels of Zn and Mn were low and urine levels of these cations were high, suggesting renal wasting and consistent with a loss of transporter function. Functional studies of the variant were not performed.
In 2 unrelated patients with CDG2N, Park et al. (2015) identified compound heterozygous mutations in the SLC39A8 gene (608732.0001-608732.0004). The mutations in the first patient were found by whole-exome sequencing; mutations in the second patient were found by direct sequencing of the SLC39A8 gene in patients with unknown glycosylation defects. Functional studies of the variants were not performed, but the patients had no detectable serum or urinary manganese, consistent with a loss of transporter function.
Inflammatory Bowel Disease (Crohn Disease)
Li et al. (2016) screened 91,713 functional SNP loci in coding regions in 10,523 individuals with inflammatory bowel disease and in 5,726 controls, and identified an association between Crohn disease (see 266600) and a polymorphism in the SLC39A8 gene (A391T; 608732.0005). The association was replicated in 2 additional cohorts (combined metaanalysis, p = 5.55 x 10(-13)). In addition, the authors found the risk allele to be associated with altered colonic mucosal microbiome composition in both healthy controls and patients with Crohn disease. Noting that the A391T variant previously had been associated with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia, they suggested that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases, including Crohn disease.
Some inbred mouse strains are resistant to cadmium (Cd)-induced testicular necrosis, and the autosomal recessive resistant phenotype has been named 'Cdm.' Dalton et al. (2005) found that the wildtype Cdm allele, which confers sensitivity to testicular necrosis, is encoded by the Slc39a8 gene. The gene was identified by positional cloning. Expression of the Slc39a8 gene in cultured mouse fibroblasts resulted in a 10-fold increase in the rate of Cd influx and accumulation, and a 30-fold increase in sensitivity to Cd-induced cell death. Although there were no nucleotide differences in Slc39a8 mRNA or splice site junctions between Cd-resistant and Cd-sensitive mice, gene expression was prominent in the vascular endothelial cells of the testis of strains of sensitive mice, but absent in those cells of resistant strains, suggesting that there is a genetic basis for differential tissue expression of this gene.
Wang et al. (2011) generated a homozygous mutant mouse with a hypomorphic Slc39a8 allele. The mice had dramatically decreased Slc39a8 expression in the embryo, fetus, placenta, and visceral yolk sac compared to wildtype. Additional genetic studies suggested that global complete knockdown of the gene (Slc39a8 -/-) would be embryonic lethal.
Galvez-Peralta et al. (2012) found that mice homozygous for a hypomorphic Slc39a8 allele had stunted growth, severe anemia, dysregulation of hematopoiesis, and failure of multiple organs, such as spleen, liver, kidney, and lung, to develop normally in utero, all of which ultimately resulted in neonatal lethality. Homozygous mutant mice had decreased zinc and iron levels in multiple tissues. The findings indicated that Slc39a8 is indispensable for proper embryonic development, and highlighted the importance of zinc homeostasis during this period.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human SLC39A8 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning). 3D imaging revealed that Slc39a8 homozygous knockout embryos at E14.5 had heart morphologic defects, including ventricular septal defects, absent sternum, small chest cavity, and small liver.
A391T Polymorphism
To investigate the mechanism by which the SLC39A8 polymorphism A391T (608732.0005) might increase the risk of Crohn disease (see 266600), Nakata et al. (2020) generated a knockin mouse model introducing an Slc39a8 A393T variant, corresponding to the human SLC39A8 polymorphic variant. Using inductively coupled plasma mass spectrometry to quantify trace elements in whole blood and tissues, the authors observed markedly reduced manganese (Mn) levels in whole blood of mutant mice. They noted that levels of zinc and iron were not altered, suggesting a specific requirement of Slc39a8 in maintaining Mn levels. Analysis of tissue Mn revealed reduced levels in the liver and colon of mutant mice compared to controls. Transmission electron microscopy of the distal colon showed that the glycocalyx in the mutant mice was sparse and significantly shorter than in wildtype mice. By FISH targeting of the bacterial EUB338 gene, the authors detected bacterial invasion in the inner mucus layer of the colon, and intestinal permeability assays showed markedly increased permeability in the mutant mice compared to wildtype mice. Immunostaining of whole colons showed that mutant mice had more numerous and larger isolated lymphoid follicles than wildtype mice, suggesting that bacterial invasion in the inner mucus layer induces maturation of isolated lymphoid follicles, consistent with indolent inflammation driven by microbiota. The mutant mice also were more susceptible to DSS-induced colitis than wildtype mice. Wildtype mice on a Mn-depleted diet exhibited increased gut permeability, reduced thickness of the inner mucus layer, penetration by commensal bacteria, and morphologic defects in the glycocalyx. The authors concluded that there is a critical role for manganese and the Mn transporter SLC39A8 in regulating intestinal barrier function.
Using CRISPR/Cas9-mediated knockin, Sunuwar et al. (2020) generated a mouse model with a Zip8 A393T change, corresponding to the human ZIP8 (SLC39A8) A391T variant, and investigated changes in manganese (Mn) homeostasis. The mutant mice showed reduced Mn levels in blood, liver, and kidney, with elevated biliary Mn excretion. In addition, the knockin mice were more susceptible to chemically induced colitis, showing greater weight loss and likelihood of rectal bleeding, as well as more severe and more prolonged inflammation on histopathology.
In 6 children of Hutterite descent and in 2 sibs, born of consanguineous Egyptian parents, with congenital disorder of glycosylation type IIn (CDG2N; 616721), Boycott et al. (2015) identified a homozygous c.112G-C transversion (c.112G-C, NM_022154.5) in exon 1 of the SLC39A8 gene, resulting in a gly38-to-arg (G38R) substitution at a highly conserved residue within the cytoplasmic domain. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the families. It was found in heterozygous state in 2 of 15,930 alleles in the ExAC database and at low frequency among Hutterite Lehrerleut controls (1.7%) and Dariusleut (3.8%) controls. Haplotype analysis did not show a common founder effect for the Hutterite and Egyptian patients, suggesting that the mutation resulted from a recurrent event. Patient cells showed normal localization of the mutant protein, but blood levels of Zn and Mn were low and urine levels of these cations were high, suggesting renal wasting and consistent with a loss of transporter function. Functional studies of the variant were not performed.
In a female infant, born of unrelated German parents, with CDG2N, Park et al. (2015) identified compound heterozygous mutations in the SLC39A8 gene: G38R and a c.1019T-A transversion in exon 6, resulting in an ile340-to-asn (I340N; 608732.0002) substitution at a highly conserved residue in transmembrane domain V, which is part of the ion channel. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The I340N variant was not found in the ExAC database. Functional studies of the variants were not performed, but the patient had no detectable serum or urinary manganese, consistent with a loss of transporter function.
For discussion of the c.1019T-A transversion (c.1019T-A, NM_022154.5) in exon 6 of the SLC39A8 gene, resulting in an ile340-to-asn (I340N) substitution, that was found in compound heterozygous state in a patient with congenital disorder of glycosylation type IIn (CDG2N; 616721) by Park et al. (2015), see 608732.0001.
In a girl with congenital disorder of glycosylation type IIn (CDG2N; 616721), Park et al. (2015) identified compound heterozygous mutations in the SLC39A8 gene: the paternal allele carried both a c.97G-A transition (c.97G-A, NM_022154.5), resulting in a val33-to-met (V33M) substitution, and a c.1004G-C transversion (c.1004G-C, NM_022154.5), resulting in a ser335-to-thr (S335T) substitution, and the maternal allele carried a c.610G-T transversion, resulting in a gly204-to-cys (G204C; 608732.0004) substitution. All substitutions occurred at conserved residues. Although both substitutions on the paternal allele were possibly causative, the S335T substitution lies within the transmembrane domain V, which is part of the ion channel. The mutations were found by direct sequencing of the SLC39A8 gene in a cohort of unsolved cases with impaired glycosylation. Functional studies of the variants were not performed, but the patient had undetectable serum and urinary levels of manganese.
For discussion of the c.610G-T transversion (c.610G-T, NM_022154.5) in the SLC39A8 gene, resulting in a gly204-to-cys (G204C) substitution, that was found in compound heterozygous state in a patient with congenital disorder of glycosylation type IIn (CDG2N; 616721) by Park et al. (2015), see 608732.0003.
Li et al. (2016) screened 91,713 functional SNP loci in coding regions in 10,523 individuals of European ancestry with inflammatory bowel disease (IBD; see 266600), including 5,742 cases of Crohn disease (CD), 4,583 cases of ulcerative colitis, and 198 unclassified cases of IBD, and in 5,726 controls. They identified an association between CD and an A391T polymorphism in the SLC39A8 gene, and replicated the association in 2 additional cohorts, including 1,096 pediatric CD cases and 551 individuals with IBD (combined metaanalysis, p = 5.55 x 10(-13)). Analysis of the microbial composition of lavage samples from the cecum and sigmoid colon of 38 SLC39A8 391T carriers and 133 noncarriers in the Mucosal Luminal Interface cohort showed that the risk allele was associated with an altered microbiome in both healthy controls and patients with CD. The SLC39A8-associated shifts in the composition of gut microbiota strongly overlapped with changes observed in CD and obesity. Noting that the A391T variant previously had been associated with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia, the authors suggested that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases, including Crohn disease.
Sunuwar et al. (2020) analyzed data from human genomewide association studies of human blood plasma and the IgG N-glycome, and observed that the SLC39A8 391T variant was associated with reduced plasma triantennary N-glycans, including trisialated and trigalactosylated structures. However, there were no associations between 391T and N-glycosylation of IgG. Analysis of a CD cohort of 313 patients revealed that 3 triantennary glycan species were decreased in CD patients with the 391T variant compared with noncarriers, suggesting that the 391T-associated glycophenotype defines a distinct patient subset within Crohn disease.
Sunuwar et al. (2020) and Nakata et al. (2020) independently generated mouse models with the corresponding Slc39a8 A393T variant (see ANIMAL MODEL) and observed alterations in manganese (Mn) homeostasis, with reduced levels of Mn in blood, liver, kidney, and colon. Mutant mice showed increased intestinal permeability and were more susceptible to chemically induced colitis.
Begum, N. A., Kobayashi, M., Moriwaki, Y., Matsumoto, M., Toyoshima, K., Seya, T. Mycobacterium bovis BCG cell wall and lipopolysaccharide induce a novel gene, BIGM103, encoding a 7-TM protein: identification of a new protein family having Zn-transporter and Zn-metalloprotease signatures. Genomics 80: 630-645, 2002. [PubMed: 12504855] [Full Text: https://doi.org/10.1006/geno.2002.7000]
Boycott, K. M., Beaulieu, C. L., Kernohan, K. D., Gebril, O. H., Mhanni, A., Chudley, A. E., Redl, D., Qin, W., Hampson, S., Kury, S., Tetreault, M., Puffenberger, E. G., and 15 others. Autosomal-recessive intellectual disability with cerebellar atrophy syndrome caused by mutation of the manganese and zinc transporter gene SLC39A8. Am. J. Hum. Genet. 97: 886-893, 2015. [PubMed: 26637978] [Full Text: https://doi.org/10.1016/j.ajhg.2015.11.002]
Dalton, T. P., He, L., Wang, B., Miller, M. L., Jin, L., Stringer, K. F., Chang, X., Baxter, C. S., Nebert, D. W. Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis. Proc. Nat. Acad. Sci. 102: 3401-3406, 2005. [PubMed: 15722412] [Full Text: https://doi.org/10.1073/pnas.0406085102]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Galvez-Peralta, M., He, L., Jorge-Nebert, L. F., Wang, B., Miller, M. L., Eppert, B. L., Afton, S., Nebert, D. W. ZIP8 zinc transporter: indispensable role for both multiple-organ organogenesis and hematopoiesis in utero. PLoS One 7: e36055, 2012. Note: Electronic Article. [PubMed: 22563477] [Full Text: https://doi.org/10.1371/journal.pone.0036055]
Li, D., Achkar, J.-P., Haritunians, T., Jacobs, J. P., Hui, K. Y., D'Amato, M., Brand, S., Radford-Smith, G., Halfvarson, J., Niess, J.-H., Kugathasan, S., Buning, C., and 28 others. A pleiotropic missense variant in SLC39A8 is associated with Crohn's disease and human gut microbiome composition. Gastroenterology 151: 724-732, 2016. [PubMed: 27492617] [Full Text: https://doi.org/10.1053/j.gastro.2016.06.051]
Nakata, T., Creasey, E. A., Kadoki, M., Lin, H., Selig, M. K., Yao, J., Lefkovith, A., Daly, M. J., Graham, D. B., Xavier, R. J. A missense variant in SLC39A8 confers risk for Crohn's disease by disrupting manganese homeostasis and intestinal barrier integrity. Proc. Nat. Acad. Sci. 117: 28930-28938, 2020. [PubMed: 33139556] [Full Text: https://doi.org/10.1073/pnas.2014742117]
Park, J. H., Hogrebe, M., Gruneberg, M., DuChesne, I., von der Heiden, A. L., Reunert, J., Schlingmann, K. P., Boycott, K. M., Beaulieu, C. L., Mhanni, A. A., Innes, A. M., Hortnagel, K., and 12 others. SLC39A8 deficiency: a disorder of manganese transport and glycosylation. Am. J. Hum. Genet. 97: 894-903, 2015. [PubMed: 26637979] [Full Text: https://doi.org/10.1016/j.ajhg.2015.11.003]
Sunuwar, L., Frkatovic, A., Sharapov, S., Wang, Q., Neu, H. M., Wu, X., Haritunians, T., Wan, F., Michel, S., Wu, S., Donowitz, M., McGovern, D., Lauc, G., Sears, C., Melia, J. Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease. JCI Insight 5: e140978, 2020. [PubMed: 32897876] [Full Text: https://doi.org/10.1172/jci.insight.140978]
Taylor, K. M., Nicholson, R. I. The LZT proteins; the LIV-1 subfamily of zinc transporters. Biochim. Biophys. Acta 1611: 16-30, 2003. [PubMed: 12659941] [Full Text: https://doi.org/10.1016/s0005-2736(03)00048-8]
Wang, B., He, L., Dong, H., Dalton, T. P., Nebert, D. W. Generation of a Slc39a8 hypomorph mouse: markedly decreased ZIP8 Zn(2+)/(HCO-(3))2 transporter expression. Biochem. Biophys. Res. Commun. 410: 289-294, 2011. [PubMed: 21658371] [Full Text: https://doi.org/10.1016/j.bbrc.2011.05.134]