Alternative titles; symbols
HGNC Approved Gene Symbol: SLC39A13
SNOMEDCT: 773276004;
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38) : 11:47,407,276-47,416,500 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p11.2 | Ehlers-Danlos syndrome, spondylodysplastic type, 3 | 612350 | Autosomal recessive | 3 |
Zinc is an essential cofactor for hundreds of enzymes. It is involved in protein, nucleic acid, carbohydrate, and lipid metabolism, as well as in the control of gene transcription, growth, development, and differentiation. SLC39A13 belongs to a subfamily of proteins that show structural characteristics of zinc transporters (Taylor and Nicholson, 2003).
By searching databases for sequences similar to a unique motif within LIV1 (SLC39A6; 608731), Taylor and Nicholson (2003) identified SLC39A13, which they designated LZT-Hs9. The deduced 364-amino acid protein contains a long N terminus, followed by 8 putative transmembrane 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.
Using in situ hybridization, Fukada et al. (2008) found that Slc39a13 was highly expressed in mouse bone and eye. Slc39a13 was expressed in osteoblasts of tibia and alveolar bone, in proliferative zone of growth plate, in odontoblasts of the forming dentin crown in molar teeth, and in fibroblasts of the reticular layer of skin. Immunohistochemical analysis showed that Slc39a13 localized in the perinuclear region of osteoblasts, chondrocytes, pulpal cells, and fibroblasts and was mainly associated with the Golgi apparatus. Fukada et al. (2008) concluded that SLC39A13 is expressed in cells essential for connective tissue development.
Bin et al. (2011) noted that SLC39A13, which they called ZIP13, contains an N-terminal pro-ala-leu (PAL) zinc-dependent processing site and a his-glu-x-x-his (HExxH) zinc-binding motif, both of which are found in the LZT family of zinc transporters. In ZIP13, the HExxH motif is located within transmembrane domain 5. ZIP13 also has a putative zinc-binding HN motif in transmembrane domain 4. Bin et al. (2011) identified a cleavable endoplasmic reticulum (ER) signal peptide N-terminal to the PAL motif in ZIP13. Immunocytochemical analysis revealed that ZIP13 colocalized with a Golgi marker and partially with an ER marker. Protease accessibility experiments revealed that both the N and C termini of ZIP13 were luminal.
Hartz (2004) mapped the SLC39A13 gene to chromosome 11p11.2 based on an alignment of the SLC39A13 sequence (GenBank AK098651) with the genomic sequence.
Using reducing and nonreducing SDS-PAGE, immunoprecipitation analysis, and crosslinking experiments, Bin et al. (2011) showed that ZIP13 formed homodimers. Overexpression of ZIP13 in HEK293 cells elevated intracellular zinc content and caused upregulation of the gene encoding metallothionein-1A (MT1A; 156350).
In 6 affected members of 2 consanguineous families with a spondylocheirodysplastic form of Ehlers-Danlos syndrome (EDSSPD3; 612350), Giunta et al. (2008) identified homozygosity for a 9-bp in-frame deletion in exon 4 of the SLC39A13 gene (608735.0001).
Fukada et al. (2008) identified a homozygous loss-of-function mutation in the SLC39A13 gene (G74D; 608735.0002) in 2 sibs with an Ehlers-Danlos syndrome-like phenotype similar to that reported by Giunta et al. (2008).
Fukada et al. (2008) found that Slc39a13 -/- mice were growth retarded and developed progressive kyphosis after 3 or 4 weeks of age. They showed changes in bone, teeth, and connective tissue reminiscent of human Ehlers-Danlos syndrome, with defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. The corresponding tissues and cells showed impaired bone morphogenic protein (BMP; see 112264) and TGF-beta (TGFB1; 190180) signaling.
In 6 affected members of 2 consanguineous families with a spondylodysplastic type of Ehlers-Danlos syndrome (EDSSPD3; 612350), Giunta et al. (2008) identified homozygosity for a 9-bp in-frame deletion in exon 4 of the SLC39A13 gene (483_491del9), resulting in the deletion of 3 amino acids (F162_164del) within the highly conserved transmembrane domain III. All of the parents and several sibs were heterozygous for the mutation, which was not found in 182 control individuals.
In 2 sibs with a spondylodysplastic type of Ehlers-Danlos syndrome (EDSSPD3; 612350), Fukada et al. (2008) identified a homozygous G-to-A transition at nucleotide 221 in the SLC39A13 cDNA, resulting in a nonconservative gly74-to-asp (G74D) substitution. G74 is located in the second transmembrane domain of SLC39A13 and is conserved in vertebrates from fish to humans.
Bin, B.-H., Fukada, T., Hosaka, T., Yamasaki, S., Ohashi, W., Hojyo, S., Miyai, T., Nishida, K., Yokoyama, S., Hirano, T. Biochemical characterization of human ZIP13 protein: a homo-dimerized zinc transporter involved in the spondylocheiro dysplastic Ehlers-Danlos syndrome. J. Biol. Chem. 286: 40255-40265, 2011. [PubMed: 21917916] [Full Text: https://doi.org/10.1074/jbc.M111.256784]
Fukada, T., Civic, N., Furuichi, T., Shimoda, S., Mishima, K., Higashiyama, H., Idaira, Y., Asada, Y., Kitamura, H., Yamasaki, S., Hojyo, S., Nakayama, M., and 14 others. The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways. PLoS One 3: e3642, 2008. Note: Electronic Article. Erratum published online. [PubMed: 18985159] [Full Text: https://doi.org/10.1371/journal.pone.0003642]
Giunta, C., Elcioglu, N. H., Albrecht, B., Eich, G., Chambaz, C., Janecke, A. R., Yeowell, H., Weis, M., Eyre, D. R., Kraenzlin, M., Steinmann, B. Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome--an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am. J. Hum. Genet. 82: 1290-1305, 2008. [PubMed: 18513683] [Full Text: https://doi.org/10.1016/j.ajhg.2008.05.001]
Hartz, P. A. Personal Communication. Baltimore, Md. 6/15/2004.
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]