The Atp7b Gene and the Effects of Its Mutations
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WILSON, J. T. (2000). The Atp7b Gene and the Effects of Its Mutations. National Undergraduate Research Clearinghouse, 3. Available online at Retrieved April 30, 2017 .

The Atp7b Gene and the Effects of Its Mutations

Sponsored by: TODD ECKDAHL (
Wilson`s disease is a very rare disease, occurring in only 1 in 33,000 people. On average, 1 in 90 people are carriers for this disease. Wilson`s disease is a disease that causes copper to accumulate in the body. This copper accumulation causes physiological, as well as neurological defects . This paper will briefly discuss the history of the disease, some common symptoms, what mutations cause the disease, and some treatments and possible cures

Wilson`s disease is a disease that causes copper accumulation in the liver. It has also been known to cause copper accumulation in the brain, cornea, kidney, and some other tissues (Baban and Hubbs, 1997). This disease affects hepatic function, and nervous system function. Some neurological symptoms that can occur are tremor of the extremities (increased especially with excitement), ataxic gait, and the patient is often easily agitated and anxious. If treatment is not given, symptoms often progress to severe mental illness, aphonia, and severe tremor (Walshe and Cox, 1998). Baban and Hubbs said that it has "an autosomal recessive inheritance pattern." This disease occurs because of a genetic mutation on the "long arm of the 13th chromosome near the esterase D locus" (Baban, Hubbs, 1997). This affects the production of an enzyme needed in copper transport and excretion by the liver. Wilson`s disease can also cause hemolysis in the blood, which causes anemia. Many times a diagnosis of Wilson`s disease is hard to reach, because the symptoms that occur towards the beginning of the disease can be misleading. Shimizu and Nakazono reported an 8-month old boy who had hypocaeruloplaminaemia, but had normal liver function and wasn`t anemic. He also had normal urinary copper excretion. Since he had no clinical symptoms or signs of Wilson`s disease, Shimizu and Nakazono screened for the Wilson`s disease gene. The child was found to have Wilson`s disease, even though he did not yet have the classic symptoms of the disease. Baban and Hubbs also described a case of a "25-year-old woman whose illness began with hemolytic anemia…" but the presence of "…hepatic, psychiatric, and neurological signs did not become apparent until five years later." Baban and Hubbs suggested that early detection has a beneficial impact on treatment. Early diagnosis also is beneficial for screening for asymptomatic relatives.While diagnosis of Wilson`s disease is difficult, once it is diagnosed, there are a number of treatments that can be done. The most common treatment today is the use of supplemental zinc (Cox et al, 1999). Zinc helps decrease the absorption of copper in the small intestines. Many of the chelator (medicines that flush copper out of the body) treatments, such as penicillamine, that have been established over the years have shown serious side effects. Plasma exchange has also proven to be an effective treatment against Wilson`s disease (Clark et al, 1998). Copper has shown to build up in the bloodstream, and plasma exchange helps reduce the amount of copper, until other measures have been taken. For patients with severe accumulation of copper in the body, a liver transplant is often necessary (Chang et al, 2000).

Wilson’s disease is an autosomal recessive disease (Walsh, 1998). This means that two copies of the defective gene are required to actually express the gene. The Wilson’s disease locus has been assigned to chromosome 13q14.3 (Brahms, 1993) The gene is 6642 bases long, and codes for a P-type ATPase protein (NCBI homepage, 1999). This protein helps to excrete excess copper in the body. In the defective version of this gene, Wilson’s disease is expressed which causes copper not to be excreted, and accumulates in the liver and neural tissue. The Wilson’s disease gene has been isolated and cloned many different ways, but one way has been used most overall, and is now the preferred method. First of all, genomic DNA is isolated from peripheral blood tissue. Next, 25 sets of oligonucleotide primers are prepared to amplify all exons except exon 1. PCR is then carried out to amplify the DNA. Finally, DNA sequencing analysis was carried out, and mutations would then be found (Shimizu, 1997). According to the Wilson’s Disease Association homepage (1999), there are over 30different point mutations that can cause Wilson`s disease. An A to a C mutation at nucleotide 2334, is the mutation that is found most often in Wilson’s disease patients (Shimizu, 1997). This mutation alters the reading frame of the gene product, and results in truncation of the ATPase protein. In 85% all WND patients an arginine-to-leucine mutation occurred near the phosphorylation site from this mutation (ExPASy homepage, 1999). Gene analysis however is not usually used to diagnose this disease, since most of the symptoms do not show up until early adulthood, and in most patients there is no family history of the disease (Baban, 1997).

The Wilson`s disease gene is most often found in the liver, kidneys, and placenta (Cox et al, 1999). The gene codes for a copper binding protein in these tissues. This protein has 14 different domains, which include six copper binding, four transmembrane, a phosphate, a transduction, a phosphorylation and an ATP binding (Chang et al, 2000). With a mutation in this gene, patients can not excrete copper, and therefore have the list of symptoms referred to above. The protein that is made with this gene is one that carries copper across membranes and allows for excretion. The mutant version of this protein will not bind to copper which in turn causes accumulation of copper in the liver, kidney and neural tissue. Figure 1 shows a gene map with the most common mutation, and protein change due to this mutation.

Diagnosis of Wilson`s disease is often a very hard thing to accomplish. One reason, which was mentioned above, is that the symptoms are often misleading to other disorders. Another reason is that there are so many mutations, that a standard genetic test is not practical. However, linkage tests are practical for family members of diseased patients (Cox et al, 1999) This is due to the fact that most of the mutations in Wilson`s disease are family linked. The most common way to detect this disease is to do a blood test. Elevated levels of copper in the blood stream are often the first signal to this disease (Chang et al, 2000). Kayser-Fleisher rings present in the cornea of the eye are another way to help diagnose this disease (Baban, Hubbs, 1997). Treatment of the disease can vary in many ways. One of the more common ways to treat this disease is with drug intervention. Trietine has been shown to successfully manage the disease (Walshe and Cox, 1998). This helped reduce the amount of copper levels in the body. Another form of treatment for Wilson`s disease is plasma transfusion. Clark et al. has shown that plasma transfusion greatly reduces the amount of copper in the bloodstream and the body. This prevented further "hemolytic anemia, and provides clinical stabilization until liver transplantation can be performed" (Clarke et al., 1998). Although this seems to be a temporary fix, it is often the only hope for patients whose disease is highly elevated. Administering a low copper diet, along with zinc acetate to reduce copper absorption, causes copper levels to drop dramatically in many patients. Ammonium tetrathiomolybdate is another new possible treatment. This "resulted in dramatic improvement, and the patient continues to do well," (Baban, Hubbs, 1997). The ammonium tetrathiomolybdate was shown to bind to copper, and help in the excreting process. No cures have yet been found for the disease. An area that has not been explored yet is the possibility of ex vivo gene therapy. This is where cells from the diseased tissue are removed good copies of the gene are inserted into the cells, and then replaced into the diseased tissue. This has sometimes been shown to allow the new genes to replicate and express themselves, causing the disease to subside or go away. It is in my opinion that this would be a viable area of research for a possible cure for Wilson`s disease.

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