Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 601416

SOLUTE CARRIER FAMILY 39 (ZINC TRANSPORTER), MEMBER 7; SLC39A7

Alternative titles; symbols

ZRT- AND IRT-LIKE PROTEIN 7; ZIP7

D6S2244E
KE4, MOUSE, HOMOLOG OF; HKE4

HGNC Approved Gene Symbol: SLC39A7

Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38) : 6:33,200,867-33,204,437 (from NCBI)

Gene-Phenotype Relationships

Location Phenotype Phenotype MIM number Inheritance Phenotype mapping key
6p21.32 Agammaglobulinemia 9, autosomal recessive 619693 Autosomal recessive 3

TEXT

Description

Zinc is an essential cofactor for more than 50 classes 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. Zinc cannot passively diffuse across cell membranes and requires specific transporters, such as SLC39A7, to enter the cytosol from both the extracellular environment and the intracellular storage compartments (summary by Taylor et al., 2004).

SLC39A7 regulates zinc (Zn(2+)) egress from the endoplasmic reticulum into the cytoplasm (summary by Anzilotti et al., 2019).

Cloning and Expression

Among the many non-HLA genes that have been identified in the region of the major histocompatibility complex (6p21.3) in mouse and human are the genes symbolized Ke4 and Ke6 in the mouse. Ando et al. (1996) stated that the function of these genes is unknown, although Ke6 may be involved in the manifestation of polycystic kidney disease (PKD; 173900) because of its aberrant expression in 2 different murine models of PKD (Aziz et al., 1993; Aziz et al., 1994). Ando et al. (1996) isolated cDNA clones corresponding to the human Ke4 and Ke6 (601417) genes (designated HKE4 and HKE6 by them). The predicted amino acid sequences of HKE4 and HKE6 exhibit 81.5 and 85.6% identity to the mouse homologs, respectively. Ando et al. (1996) speculated that HKE4 may encode a membrane protein with histidine-rich charge clusters.

Taylor et al. (2004) cloned HKE4. The deduced 469-amino acid protein has a calculated molecular mass of 50 kD. It contains a cleavable signal peptide, a long cytosolic N terminus, 8 transmembrane domains, and a short C terminus. The N-terminal half contains several histidine-rich repeats, and HKE4 has a central catalytic zinc-binding site and a cytoplasmic dileucine motif that predicts retention in the endoplasmic reticulum (ER). Deglycosylation experiments and Western blot analysis indicated that HKE4 is a protein of about 50 kD that contains no N-linked glycans. Fluorescence microscopy of Chinese hamster ovary cells transfected with HKE4 revealed staining of a perinuclear network and colocalization with an ER marker protein. RNA dot blot analysis indicated low but ubiquitous expression of HKE4, with highest levels in placenta, liver, pituitary, pancreas, salivary gland, kidney, and prostate.

Gene Function

By transient transfection in Chinese hamster ovary cells, Taylor et al. (2004) showed that HKE4 increased intracellular free zinc in a time-, temperature-, and concentration-dependent manner.

Mapping

Ando et al. (1996) determined that the HKE4 and HKE6 genes are located at the centromeric end of the HLA region on human 6p21.3.

Kikuti et al. (1997) examined YAC clone Y42, which contains the MHC class II region of chromosome 6q21.3. This region has a relatively high gene density. They identified the following human genes (in order from centromere toward telomere): HSET (603763)--HKE1.5--HKE2--HKE3--RING1--(602045)--HKE6 (601417)--HKE4--RXRB (180246)--COL11A2 (120290)--DPB2.

Molecular Genetics

In 6 patients from 5 unrelated families with autosomal recessive agammaglobulinemia-9 (AGM9; 619693), Anzilotti et al. (2019) identified compound heterozygous or homozygous mutations in the SLC39A7 gene (see, e.g., 601416.0001-601416.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variants were either absent from or present at a low frequency in the heterozygous state in gnomAD. Studies of patient cells and HEK293 cells transfected with the mutations showed that the mutant proteins were expressed normally and localized properly to the endoplasmic reticulum. However, Xenopus oocytes transfected with 2 of the mutations showed decreased zinc transporter activity compared to controls. Knockin mutant mouse models recapitulated the phenotype with a severe defect in B-cell development. The authors concluded that proper zinc dynamics are essential for proper B-cell development and that the disease alleles are likely hypomorphic with partial loss of SLC39A7 function.

Animal Model

Anzilotti et al. (2019) found that knockin mice carrying hypomorphic Slc39a7 mutations, including the P198A mutation (orthologous to the human P190A mutation, 601416.0001), demonstrated profound B-cell deficiency with variable growth and skin defects. Homozygosity for a null allele was embryonic lethal. Detailed studies of mutant mice with hypomorphic mutations showed impaired B-cell development affecting multiple development pathways. Other findings included decreased levels of cytoplasmic zinc, evidence of accelerated death of normal B cells, decreased phosphorylation of signaling molecules downstream of the pre-B cell and B-cell receptors (BCR), and defective signaling by the BCR during positive selection.

ALLELIC VARIANTS 5 Selected Examples):

.0001 AGAMMAGLOBULINEMIA 9, AUTOSOMAL RECESSIVE

SLC39A7, PRO190ALA
SNP: rs563866464, gnomAD: rs563866464, ClinVar: RCV002040268, RCV002271714

In 2 brothers (P1 and P2), born of unrelated parents of northern European descent, with autosomal recessive agammaglobulinemia-9 (AGM9; 619693), Anzilotti et al. (2019) identified compound heterozygous missense mutations in the SLC39A7 gene: a C-to-G transversion, resulting in a pro190-to-ala (P190A) substitution, and a G-to-A transition, resulting in a glu363-to-lys (E363K; 601416.0002) substitution. An unrelated patient (P6) was compound heterozygous for P190A and a T-to-C transition in the SLC39A7 gene, resulting in a leu217-to-pro (L217P; 601416.0003) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The P190A variant was found once in the gnomAD database; E363K was not present in gnomAD. Fibroblasts derived from P1 and P2 and HEK293 cells transfected with the mutations showed normal SLC39A7 protein levels and proper localization to the ER. In vitro functional expression studies in Xenopus oocytes transfected with the mutations showed normal protein expression and normal cytoplasmic zinc levels, but decreased zinc transporter activity compared to controls, consistent with a hypomorphic effect.

.0002 AGAMMAGLOBULINEMIA 9, AUTOSOMAL RECESSIVE

SLC39A7, GLU363LYS
SNP: rs771311186, ClinVar: RCV001810391

For discussion of the G-to-A transition in the SLC39A7 gene, resulting in a glu363-to-lys (E363K) substitution, that was found in compound heterozygous state in 2 sibs with autosomal recessive agammaglobulinemia-9 (AGM9; 619693) by Anzilotti et al. (2019), see 601416.0001.

.0003 AGAMMAGLOBULINEMIA 9, AUTOSOMAL RECESSIVE

SLC39A7, LEU217PRO
SNP: rs1170038377, ClinVar: RCV001810392, RCV003728013

In a girl (P3) of northern European descent with autosomal recessive agammaglobulinemia-9 (AGM9; 619693) Anzilotti et al. (2019) identified compound heterozygous mutations in the SLC39A7 gene: a T-to-C transition, resulting in a leu217-to-pro (L217P) substitution, and a C-to-T transition, resulting in gln372-to-ter (Q372X; 601416.0004) substitution. Another patient (P6) of northern European descent was compound heterozygous for L217P and P190A (601416.0001). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The L217P variant was not present in the gnomAD database; Q372X was found 8 times, only in the heterozygous state. HEK293 cells transfected with the mutations showed normal protein levels and cellular localization to the ER for L217P; the nonsense mutation was expressed as a truncated protein that also showed proper cellular localization. Additional functional studies of the variants were not performed, but they were predicted to be hypomorphic mutations.

.0004 AGAMMAGLOBULINEMIA 9, AUTOSOMAL RECESSIVE

SLC39A7, GLN372TER
SNP: rs201790479, gnomAD: rs201790479, ClinVar: RCV001810393

For discussion of the C-to-T transition in the SLC39A7 gene, resulting in a gln372-to-ter (Q372X) substitution, that was found in compound heterozygous state in a patient with autosomal recessive agammaglobulinemia-9 (AGM9; 619693) by Anzilotti et al. (2019), see 601416.0003.

.0005 AGAMMAGLOBULINEMIA 9, AUTOSOMAL RECESSIVE

SLC39A7, THR395ILE
SNP: rs1416107120, gnomAD: rs1416107120, ClinVar: RCV001810394

In a girl (P5) of Hispanic descent with autosomal recessive agammaglobulinemia-9 (AGM9; 619693), Anzilotti et al. (2019) identified a homozygous C-to-T transition in the SLC39A7 gene, resulting in a thr395-to-ile (T395I) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was found twice in the heterozygous state in the gnomAD database. HEK293 cells transfected with the mutation showed normal protein levels and cellular localization to the ER. Additional functional studies of the variant were not performed, but it was predicted to have a hypomorphic effect.

REFERENCES

  1. Ando, A., Kikuti, Y. Y., Shigenari, A., Kawata, H., Okamoto, N., Shiina, T., Chen, L., Ikemura, T., Abe, K., Kimura, M., Inoko, H.cDNA cloning of the human homologues of the mouse Ke4 and Ke6 genes at the centromeric end of the human MHC region. Genomics 35: 600-602, 1996. [PubMed: 8812499] [Full Text: https://doi.org/10.1006/geno.1996.0405\]
  2. Anzilotti, C., Swan, D. J., Boisson, B., Deobagkar-Lele, M., Oliveira, C., Chabosseau, P., Engelhardt, K. R., Xu, X., Chen, R., Alvarez, L., Berlinguer-Palmini, R., Bull, K. R., and 33 others.An essential role for the Zn(2+) transporter ZIP7 in B cell development. Nature Immun. 20: 350-361, 2019. [PubMed: 30718914] [Full Text: https://doi.org/10.1038/s41590-018-0295-8\]
  3. Aziz, N., Maxwell, M. M., Brenner, B. M.Coordinate regulation of 11-beta-HSD and Ke6 gene in cpk mouse: implications for steroid metabolic defect in PKD. Am. J. Physiol. 267: F791-F797, 1994. [PubMed: 7977782] [Full Text: https://doi.org/10.1152/ajprenal.1994.267.5.F791\]
  4. Aziz, N., Maxwell, M. M., St.-Jacques, B., Brenner, B. M.Downregulation of Ke 6, a novel gene encoded within the major histocompatibility complex, in murine polycystic kidney disease. Molec. Cell. Biol. 13: 1847-1853, 1993. Note: Erratum: Molec. Cell. Biol. 13: 6614 only, 1993. [PubMed: 8441417] [Full Text: https://doi.org/10.1128/mcb.13.3.1847-1853.1993\]
  5. Kikuti, Y. Y., Tamiya, G., Ando, A., Chen, L., Kimura, M., Ferreira, E., Tsuji, K., Trowsdale, J., Inoko, H.Physical mapping 220 kb centromeric of the human MHC and DNA sequence analysis of the 43-kb segment including the RING1, HKE6, and HKE4 genes. Genomics 42: 422-435, 1997. [PubMed: 9205114] [Full Text: https://doi.org/10.1006/geno.1997.4745\]
  6. Taylor, K. M., Morgan, H. E., Johnson, A., Nicholson, R. I.Structure-function analysis of HKE4, a member of the new LIV-1 subfamily of zinc transporters. Biochem. J. 377: 131-139, 2004. [PubMed: 14525538] [Full Text: https://doi.org/10.1042/BJ20031183\]

Contributors:

Cassandra L. Kniffin - updated : 01/05/2022
Patricia A. Hartz - updated : 6/18/2004
Jennifer P. Macke - updated : 10/13/1997

Creation Date:

Victor A. McKusick : 9/9/1996

Edit History:

carol : 01/18/2022
carol : 01/11/2022
alopez : 01/10/2022
ckniffin : 01/05/2022
carol : 04/12/2013
terry : 4/19/2011
alopez : 9/14/2007
mgross : 6/24/2004
terry : 6/18/2004
psherman : 7/21/2000
psherman : 6/19/2000
alopez : 4/22/1999
alopez : 10/27/1997
alopez : 10/13/1997
jamie : 10/23/1996
jamie : 10/16/1996
mark : 9/11/1996
terry : 9/10/1996
mark : 9/10/1996
mark : 9/9/1996