Copper is an element essential for life, but excessive copper can be toxic or even lethal to the cell. Therefore, cells have developed sophisticated ways to maintain a critical copper balance, with the intake, export, and intracellular compartmentalization or buffering of copper strictly regulated. The 2 related genes ATP7A (300011) and ATP7B (606882), responsible for the human diseases Menkes syndrome (309400) and Wilson disease (277900), respectively, are involved in copper export. In S. cerevisiae, the copper uptake genes CTR1, CTR2, and CTR3 have been identified, and in human the CTR1 and CTR2 (603088) genes have been identified.

Zhou and Gitschier (1997) isolated a human cDNA encoding COPT1, which they called CTR1, by functional complementation of the yeast high-affinity copper uptake mutant ctr1. The deduced 190-amino acid human CTR1 protein is similar to yeast CTR1 and Arabidopsis COPT1, a copper transporter also isolated by functional complementation of yeast ctr1. All 3 predicted proteins have 3 transmembrane domains and an N terminus that is rich in methionine and serine residues; the N terminus of human CTR1 is also abundant in histidines. Northern blot analysis detected 2 major CTR1 transcripts of approximately 2 kb and 5.5 kb and a less abundant transcript of about 8.5 kb in all human organs and tissues examined.

By genomic sequence analysis, Moller et al. (2000) determined that the CTR1 gene contains 4 exons.

Zhou and Gitschier (1997) found that the 3-prime untranslated region of the human CTR1 gene contains a CA repeat marker (D9S262) that had previously been mapped to 9q31-q32. By analysis of YAC clones, they showed that CTR1 and CTR2, which is also located in 9q31-q32, are not adjacent genes. Moller et al. (2000) identified an apparent CTR1 pseudogene (CTR1P) on 3q25-q27.

Aller and Unger (2006) reported the 6-angstrom projection structure of human CTR1. The projection of CTR1 revealed a symmetrical trimer less than 40 angstroms wide. The center 3-fold axis of each trimer formed a region of very low electron density likely to be involved in copper translocation. The structure of the putative pore was more closely related to channel proteins than to typical primary and secondary active transporters.

Zhou and Gitschier (1997) proposed that CTR1 is a high-affinity copper uptake gene because it could complement the yeast ctr1 mutation, it could rescue multiple defects in ctr1 yeast, its expression in ctr1 yeast increased the concentration of cellular copper, and its overexpression in yeast led to a vulnerability to the toxicity of copper overload.

Moller et al. (2000) found that cells expressing CTR1 but not those expressing CTR2 showed a dramatic hyperaccumulation of radioactive copper, comparable to that seen in fibroblasts from Menkes disease patients. However, in contrast to the Menkes syndrome fibroblasts, the CTR1-expressing fibroblasts had an efflux rate similar to normal fibroblasts.

By cross-linking CTR1 transiently expressed in HEK293 cells, Lee et al. (2002) demonstrated that CTR1 forms a homotrimer as part of a copper transport channel. Functional assays revealed that it stimulates the initial rate of radiolabeled copper uptake. CTR1 transports copper with high affinity in a time-dependent and saturable manner and is copper-specific. Transport is an energy-independent process and is stimulated by extracellular acidic pH and high K+ concentrations.

Using pulse-chase labeling followed by immunoprecipitation, Klomp et al. (2002) found that endogenous CTR1 is synthesized in HeLa cells as a 28-kD precursor containing N-linked oligosaccharides, and it is processed into a 35-kD mature protein. Immunofluorescent microscopy showed that the subcellular localization of CTR1 differed between cell types. In some cells, including HeLa, lung, and hepatocellular carcinoma cell lines, it predominantly localized in a vesicular perinuclear compartment, while in other cells, including choriocarcinoma and colon carcinoma cell lines, it localized predominantly at the plasma membrane. The localization of CTR1 was not influenced by copper concentration, but inhibition of endocytosis caused a partial redistribution of CTR1 to the cell surface of HeLa cells.

Using accessibility of epitopes to antibody before or after cell permeabilization, Eisses and Kaplan (2002) determined that CTR1, expressed at the surface of transfected sf9 insect cells, has an extracellular N terminus and an intracellular C terminus. Using mutagenic analysis, they determined that neither of the 2 cys residues, cys161 and cys189, play a role in copper uptake, and that glycosylation of CTR1 is not required for function.

In monozygotic twins with neurodegeneration and seizures due to copper transport defect (NSCT; 620306), Batzios et al. (2022) identified a homozygous missense mutation (R95H; 603085.0001) in the SLC31A1 gene. The mutation was identified by whole-exome sequencing. The copper level and mitochondrial respiratory chain function were reduced in patient fibroblasts compared to controls, which was improved with treatment with copper histidinate. SLC31A1 protein with the R95H mutation was normally localized in patient fibroblasts but the cells had a dilated endoplasmic reticulum.

In a Turkish patient, born to consanguineous parents, with NSCT, Dame et al. (2023) identified a homozygous missense mutation in the SLC31A1 gene (L79P; 603085.0002). The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents. The patient had low serum copper and ceruloplasmin.

To test the hypothesis that CTR1 is required for copper delivery to mammalian cells, Kuo et al. (2001) inactivated the Ctr1 gene in mice by targeted mutagenesis. They observed early embryonic lethality in homozygous mutant embryos and a deficiency in copper uptake in the brains of heterozygous animals. A study of the spatial and temporal expression pattern of Ctr1 during mouse development and adulthood further showed that Ctr1 is ubiquitously transcribed with highest expression observed in the specialized epithelia of the choroid plexus and renal tubules and in connective tissues of the eye, ovary, and testis. Similarly, Lee et al. (2001) showed that the mouse Ctr1 gene encodes a component of the copper transport machinery and that mice heterozygous for Ctr1 exhibit tissue-specific defects in copper accumulation and in the activities of copper-dependent enzymes. Mice completely deficient for Ctr1 exhibited profound growth and developmental defects and died in utero in midgestation.