Alternative titles; symbolsMETALLOTHIONEIN IAHGNC Approved Gene Symbol: MT1ACytogenetic location: 16q13 Genomic coordinates (GRCh38): 16:56,638,665-56,640,08...
Alternative titles; symbols
HGNC Approved Gene Symbol: MT1A
Cytogenetic location: 16q13 Genomic coordinates (GRCh38): 16:56,638,665-56,640,086 (from NCBI)
▼ Cloning and Expression
Karin and Richards (1982) described the molecular cloning and sequence analysis of human metallothionein transcripts. Karin et al. (1984) characterized DNA sequences that are involved in the induction of MT gene expression by cadmium and glucocorticoids.
▼ Gene Function
MTs have been postulated to detoxify metals; to play a role in zinc and copper homeostasis during development; to regulate synthesis, assembly, or activity of zinc metalloproteins; and to protect against reactive oxygen species (summary by Masters et al., 1994).
▼ Gene Family
Masters et al. (1994) described metallothioneins (MTs) as a family of low molecular weight, heavy metal-binding proteins characterized by a high cysteine content and lack of aromatic amino acids. MTs bind 7 to 12 heavy metal atoms per molecule of protein. They are ubiquitous in the animal and plant kingdoms and are found in prokaryotes. In mammals, the cysteine residues are absolutely conserved and serve to coordinate heavy metal atoms such as zinc, cadmium, and copper via mercaptide linkages. In human liver, MTs occur in 2 major forms, MT-I and MT-II (156360). In HeLa cells, MT synthesis is induced by either ionized zinc or ionized cadmium and by glucocorticoid hormones. In man, metallothioneins are encoded by at least 10 to 12 genes separated into 2 groups designated MT-I and MT-II. Masters et al. (1994) noted that, unlike MT-I and MT-II, which are expressed in most organs, MT-III (139255) expression appears to be restricted to the brain, and MT-IV is only expressed in certain stratified squamous epithelia.
Karin et al. (1984) used several different hybridization probes derived from cloned and functional human MT1 and MT2 genes to map the genes in somatic cell hybridization studies. They concluded that most of the human genes are clustered on chromosome 16. Analysis of RNA from somatic cell hybrids indicated that all hybrids that contain human chromosome 16 express both MT1 and MT2 mRNA and that expression is regulated by both heavy metal ions and glucocorticoid hormones.
In the mouse, the metallothionein genes are on chromosome 8, which has other homology to human chromosome 16; by somatic cell hybridization, Cox and Palmiter (1983) assigned the Mt-1 structural gene to mouse chromosome 8, which also carries glutathione reductase in the mouse. (By chance the human 8 also carries glutathione reductase.)
Schmidt et al. (1984) concluded that MT1 is located between PGP (172280) and DIA4 (125860) and is probably on the long arm 16cen-16q21 because APRT (102600), a 16q marker, and MT1 are both on mouse chromosome 8, whereas HB alpha (141800), a 16p marker, is on mouse chromosome 11. They stated that analysis of the involvement of the MT genes in Wilson disease (277900) and in acrodermatitis enteropathica (201100) would be of great interest.
By gel transfer hybridization analysis of the DNA from human-rodent cell hybrids, Schmidt et al. (1985) showed that chromosome 16 contains a cluster of metallothionein sequences, including 2 functional metallothionein I genes (156351 and 156352) and a functional metallothionein II gene. The remaining sequences, including a processed pseudogene, are dispersed to at least 4 other autosomes. The absence of metallothionein sequences from the X chromosome indicates that the Menkes disease mutation affects metallothionein expression by a 'trans-acting' mechanism. The processed pseudogene is on chromosome 4 and shows allelic variation (Karin and Richards, 1982). Two MT genes are on chromosome 1 but not close together: one is on the distal two-thirds of the short arm and the second probably on the long arm. One metallothionein gene is on chromosome 20 and another is on chromosome 18.
By in situ hybridization, Le Beau et al. (1985) assigned the metallothionein gene cluster to 16q22. This band is a breakpoint in 2 specific rearrangements, inv(16)(p13q22) and t(16;16)(p13;q22), found in a subgroup of patients with acute myelomonocytic leukemia. Hybridization of an MT probe to malignant cells from patients with one or the other of these rearrangements showed that the breakpoint at 16q22 splits the MT gene cluster. The findings were interpreted as indicating that the MT genes or their regulatory regions may function as an 'activating' sequence for an as yet unidentified cellular gene located at 16p13. Band 16p22 carries 2 fragile sites: the rare FRA16B and the common FRA16C. Simmers et al. (1987) showed that the specific leukemic break that is situated in the metallothionein gene cluster lies proximal to both fragile sites; therefore, neither of these fragile sites could have played a role in the breakage.
Using high-resolution in situ hybridization, Sutherland et al. (1989, 1990) corrected the mapping of the human metallothionein gene complex to 16q13. They found, furthermore, that the complex is not disrupted by the rearrangement breakpoint on 16q in the patients with myelomonocytic leukemia with abnormal eosinophils, as had previously been reported. They showed that the order is cen--MT--FRA16B--D16S4--inversion breakpoint--HB--qter.
Foster et al. (1988) indicated that 4 functional MT1 genes had been identified and mapped to 16q: MT1A, MT1B (156349), MT1E (156351), and MT1F (156352). They also characterized a fifth MT gene, MT1G (156353). West et al. (1990) mapped the cluster of MT genes in an 82.1-kb region of 16q13. Of the 14 tightly linked genes, 6 had not previously been described. The mapped genes included the single MT2 gene, MT2A, and at least 2 pseudogenes, MT1C and MT1D. The genes were flanked by the single MT2A gene at one end and a gene labeled MT1X (156359) at the other. The order of genes, beginning at the MT2A end, was 1L--1E--1K--1J--1A--1D--1C--1B--1F--1G--1H--1I. This was also the 5-prime to 3-prime direction of transcription for all the genes except MT1G, which had a tail-to-tail, head-to-head orientation to MT1F and MT1H, respectively.
▼ Animal Model
To test the proposed detoxification and homeostasis functions of mammalian MTs in vivo, Masters et al. (1994) inactivated both alleles of the Mt1 and Mt2 genes in embryonic stem cells and generated mice homozygous for these mutant alleles. These mice were viable and reproduced normally when reared under normal laboratory conditions. They were, however, more susceptible to hepatic poisoning by cadmium. This suggested to Masters et al. (1994) that these widely expressed MTs are not essential for development but do protect against cadmium toxicity.
Human Menkes disease (309400) and the murine 'Mottled' phenotype are X-linked diseases that result from copper deficiency due to mutations in ATP7A, a copper-effluxing ATPase (300011). Male mice with the Mottled-Brindled allele accumulate copper in the intestine, fail to export copper to peripheral organs, and die a few weeks after birth. Much of the intestinal copper is bound by metallothionein. To determine the function of MT in the presence of Atp7a deficiency, Kelly and Palmiter (1996) crossed Mottled-Brindled females with males that bear a targeted disruption of the Mt1 and Mt2 genes. On the metallothionein-deficient background most Mottled males as well as heterozygous Mottled females died before embryonic day 11. The authors explained the lethality in females by preferential inactivation of the paternal X chromosome in extra embryonic tissues and resultant copper toxicity in the absence of MT. In support of this hypothesis, Kelly and Palmiter (1996) found that cell lines derived from metallothionein deficient, Mottled embryos were very sensitive to copper toxicity. They concluded that MT is essential to protect against copper toxicity in embryonic placenta, providing a second line of defense when copper effluxers are defective. They also stated that MT probably protects against hepatic copper toxicity in Wilson disease and the LEC rat model in which a similar copper effluxer, ATP7B (606882), is defective, because MT accumulates to high levels in the liver in those diseases.
Beattie et al. (1998) noted that mice with targeted disruption of the metallothionein I and metallothionein II genes were more sensitive to toxic metal and oxidative stress. In addition they were larger than most strains of mice, becoming significantly heavier at age 5 to 6 weeks. At age 14 weeks, the body weight and food intake of MT-null mice was 16 and 30% higher, respectively, compared with control mice. Most 22- to 39-week-old male MT-null mice were obese. Seven-week-old MT-null also had significantly higher levels of plasma leptin (601694) and elevated expression of OB (164160), lipoprotein lipase (238600), and CCAAT enhancer binding protein alpha (189965) genes as compared with age-matched control mice. Abnormal accretion of body fat and adipocyte maturation was initiated at 5 to 7 weeks of age, possibly coincident with sexual maturation. Beattie et al. (1998) concluded that a link between MT and the regulation of energy balance is implied by these observations. They noted the possibility that obesity and the associated biochemical changes in the MT-null mice may be caused by factors other than lack of MT. For example, disruption of MT genes by homologous recombination with DNA containing various modifications may have affected other genes around this locus or may have had downstream effects on gene expression.