Wilson’s Disease is a copper transport disorder. Although the signs and symptoms of the disease were characterized by Dr. Kinnier Wilson in 1912, it wasn’t until several decades later that the metabolic cause of the disease was fully elucidated.
Familial or Inherited?
When Wilson first characterized Wilson’s Disease in 1912 he asserted that the disease was familial, but not hereditary. (Wilson, 1912) Despite his insistence, there was suspicion in the scientific community that Wilson’s Disease was an inherited disorder. In 1921 Hall reviewed Wilson’s patient cases and an additional seven cases and stated that the disease was likely inherited in a recessive pattern. Later studies also lent support to the idea that Wilson’s Disease was an inherited, recessive disorder, but up until this point all genetic analysis had been done using old patient case reports. This methodology left a lot of room for error if everything hadn’t been properly recorded in the initial case report. Finally in 1953 A.G. Bearn used genetic ratio analysis calculations, instead of patient case reports, to confirm that Wilson’s Disease is inherited in an autosomal recessive pattern. (Bearn 1953) Now that it was clear that Wilson’s Disease was hereditary, the scientific community could move on to determine what was actually causing the disease.
The Wilson’s Disease Gene– Genetics and Epigenetics:
In 1993 a suite of Nature Genetics papers were published which mapped the Wilson’s Disease gene to chromosome 13q14.3 and found that the gene codes for ATP7B, a copper-transporting ATPase that binds copper to ceruloplasmin, a copper carrying protein, and then transports the bound copper out of the cell and into the circulatory system. (Bull et. al. 1993) (Petrukhin et. al. 1993) (Tanzi et. al. 1993) Case studies have uncovered a wide variety of mutation types in the Wilson’s Disease gene that can disrupt the coding of ATP7B enough to cause Wilson’s Disease. (Bull et. al. 1993) (Petrukhin et. al. 1993) (Tanzi et. al. 1993) These mutations often vary by family and currently the information is limited to small genetic case studies. So far the mutations that have been determined to cause Wilson’s Disease include truncating mutations, splice mutations, missense mutations, splicing defects, frameshift mutations, deletions, and nonsense mutations all of different base pair lengths in different parts of the gene. Although scientists have not yet determined if there is a critical residue or region of the gene that when mutated causes Wilson’s Disease, it has been observed that the majority of these mutations disrupt the stability or activity of ATP7B in such a way that is it unable to function.
Many scientists believed that all mutations that caused Wilson’s Disease disrupted ATP7B in this way, but a new study altered this paradigm when the authors discovered a mutation that impairs ATP7B’s ability to exit the Golgi. (Braiterman et. al. 2014) The disease causing mutation induces local distortions at ATP7B’s transmembrane 1 domain which alters the interactions between transmembrane domains 1 and 2 (TM1 and TM2), thus preventing ATP7B from exiting the trans-golgi network. (Braiterman et. al. 2014) The author’s characterization of this new type of mutation and the proposed mechanism for how it functions also sheds light on the broader role of TM1 and TM2 as regulators of copper trafficking in ATP7B. (Braiterman et. al. 2014)
Recent research has looked beyond mutation of the Wilson’s Disease gene to the role of epigenetics in the regulation of the Wilson’s Disease gene. A new study characterized hepatic copper accumulation, methionine metabolism, global DNA methylation and gene expression in a mouse model for Wilson’s Disease throughout its lifespan from fetus through adulthood. (Le et. al. 2014) The authors found that there is a close relationship between copper accumulation and the decreased expression and increased methylation of several of the enzymes necessary for methionine metabolism. (Le et. al. 2014) In healthy people, S-adenosylhomocysteinase regenerates S-adenosyl homocstiene (SAH) which is the enzyme that inhibits DNA methylation.(Le et. al. 2014) The ratio of SAH to SAM (S-adenosylmethionine–the enzyme that methylates DNA) is imperative for maintaining normal DNA methylation regulation.(Le et. al. 2014) In Wilson’s Disease ATP7B is not functional due to a mutation in the WD gene. Therefore, copper accumulates in the liver. This copper accumulation inhibits S-adenosylhomocysteinase, which means that SAH is not regenerated and so it increases in concentration.(Le et. al. 2014) This throws off the SAH to SAM ratio and therefore there is more DNA methylation than normal.(Le et. al. 2014) The authors hypothesize this indicates a correlation between genetic and epigenetic regulation of the onset and later progression of Wilson’s Disease. (Le et. al. 2014) The role that epigenetics plays in Wilson’s Disease will be a new direction for research in this field in the coming years.
Copper-transporting ATPase ATP7B:
The Wilson’s Disease gene codes for the copper-transporting ATPase ATP7B. ATP7B is responsible for managing copper in the cell. THe highest concentration of ATP7B is found in hepatocytes, but it is also found in smaller concentrations in brain and kidney cells. Proteins in the ATPases family are transport proteins that use ATP to power the transport of heavy metals. ATP7B uses ATP to power the transport of copper. ATP7B facilitates the binding of copper to ceruloplasmin, the copper carrying protein, in the liver so that copper can be carried through the blood stream to other tissues that require it for metabolic processes. When copper is in excess, ATP7B packages excess copper into vesicles that are sent to the bile so that the copper can later be excreted in feces. (Turnlund 1998)
There have been homology models proposed for the structure of ATP7B. However, because ATP7B is a membrane bound protein, a crystal structure of the entire protein has not yet been accomplished. The homology model for the structure of ATP7B contains an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least two putative copper-binding sites. Figure 1 below show a homoloy model for ATP7B. (USCN)
In Wilson’s Disease, the gene coding for ATP7B is mutated and therefore ATP7B’s stability and activity are disrupted, making copper transport difficult, if not impossible.
It was possible to elucidate the role of ATP7B in Wilson’s Disease because of the similarity of ATP7B to ATP7A, another copper-transporting ATPase which is linked with Menkes Disease, another copper transport disorder. (Tanzi et. al. 1993) ATP7A is found in almost all tissues of the body except the liver, brain, and kidneys where ATP7B is found. Both ATP7A and ATP7B contain 6 heavy metal binding domains and 8 membrane spanning helices. Copper is delivered to ATP7A and ATP7B via chaperones like ATOX1. (Gourdon et. al. 2012) In 2012 a study proposed a homology model for ATP7B and ATP7A based on the crystal structures available for the individual, soluble domains by comparing them to a recently solved protein, LpCopA, from a bacterial model. (Gourdon et. al. 2012) The authors also determined that the heavy metal binding domains 5 and 6 (HMBD5 and HMBD6) are crucial for function by mapping disease causing missense mutations. (Gourdon et. al. 2012) Finally, further analysis of the HMBDs allowed the authors to propose a structural model and mechanism where the 6 HMBDs associate in three pairs and communicate via a connecting loop domain between HMBD5 and HMBD6 so that when copper is bound, the autoinhibitory HMBD6 is displaced from the ATPase protein core. (Gourdon et. al. 2012)
The Impact of Wilson’s Disease on Global Copper Metabolism:
Humans consume copper as part of our diet. The copper is then absorbed by the intestinal mucosa and transported via the portal blood to the liver. (Turnlund 1998) When copper arrives at the liver in a patient with Wilson’s Disease, ATP7B does not function properly. (Gourdon et. al. 2012) Therefore, ATP7B is unable to use copper to bind and modify the ceruloplamsin protein, which is made in the liver. Ceruloplasmin is the protein responsible for carrying copper through systemic circulation to the other tissues of the body that require copper for their enzymes. Because of this, the copper is released as free copper, meaning that it is only loosely bound to albumin or other small molecules. Free copper is not capable of being picked up by the surrounding tissues requiring copper, so free copper accumulates in the blood stream. The excess copper acts as a heavy metal to donate electrons to oxygen species resulting in reactive oxygen species such as superoxide. These reactive oxygen species can reek havoc on the patient’s system. (Kalita et. al.)
Not only does ATP7B mutation cause problems with free copper in the blood stream, but it also causes issues with accumulation of copper in vital organs such as the liver and brain. When there is excess copper in the liver of a healthy patient, ATP7B leaves the Golgi and instead works to package copper into vesicles to remove the excess copper before it damages the liver. Those vesicles are then sent out of the liver via bile. (Turnlund 1998) In a person with Wilson’s disease, ATP7B is unable to package the copper into vesicles for export from the liver via bile and subsequent excretion in feces. Therefore, the excess copper accumulates in the liver, and other vital organs, of the Wilson’s Disease patient. This copper accumulation causes an inflammatory response in the patient’s liver and brain. This inflammation leads to the symptoms we associate with Wilson’s Disease such as cirrhosis. (Turnlund 1998)
Other Pages on Wilson’s Disease: