Tuesday, January 16, 2018

Tour your code: A is for….ATP7B: "The Copper Trader"

Happy New Year! And with the new year, I'm undertaking a new endeavour on my blog. In 2018, I'm going to be taking a tour of genes found in the human genome. There are an estimated 20,000 genes in our genetic code, so I may have to be somewhat curated list. I'm going to focus on genes that aren't as commonly known in the wide world or covered by the media but have interesting functions or links to disease of interesting history. I'll be staying away from the 'famous' list because let's face it - there's already plenty of information and blog posts regarding genes like BRCA. It also happens there's at least one gene for every letter of the alphabet. So it's not hard to make the tour 26 stops from A-Z. 

I began researching the ABCs of human genes and quickly came to the realisation that gene names are well...pretty dry and terrible. Yet the genes themselves and what they produce is endlessly fascinating. So don't be perturbed by the coded names and dry nomenclature. Your genetic code is quite amazing, there just needed to be a way to identify them in a universal way, and like most standardised things practicality is more important than fun flourishes.

Human genes are actually named according to a convention set down by the HUGO Gene Nomenclature Committee (HGNC). This name and symbol means there's a standard for official gene identification in research and clinical practice, though it's also common for some genes to have 'common' names that are used in discussion in the scientific community. Genes can also be named according to their position on their respective chromosome or through standardised catalogue numbers in the various databases scientists use.

While there's a standard for human genes, there is also some gold out there in terms of gene names in other species - Sonic The Hedgehog, Tinman, INDY (I'm Not Dead Yet) are all gene names, and are all genes from the Drosophila fly. Drosophila Melanogaster is a model organism and is one of the most studied organisms. The annoying fruit fly actually plays a huge role in scientific research! And it turns out when given the opportunity, scientists will seize it.  But I digress.... 

This week: ATP7B
Common Name:  Wilson Disease Protein (WND)

Main Features:

  • Expressed in the liver and in small amounts in the brain
  • 80 000 bases of DNA sequence in total - only 7500 bases make up the protein sequence
  • Gene is located on Chromosome 13
  • Physical Location is 13q14.3
  • Consists of 13 exons (protein coding genetic segments)
  • Consists of 1465 amino acids (protein building blocks, each encoded by 3 DNA bases)
  • Produces Copper-Transporting ATPase 2
  • Protein is 165 kDa in size
  • 8 domains
  • Functions: adds copper groups to new proteins; exports copper out of liver cells into bile
  • Disease: mutations in the gene results in defective ATP7B causing Wilson's Disease

ATP7B is a gene that encodes a protein called Copper-Transporting ATPase 2. This is as a P-type ATPase. This group of proteins transport metals. 
"I whip my domain back and forth". Copper-Transporting ATPase 2. Source: Wikipedia (CC).


Every cell in the human body, except red blood cells has a duplicated copy of the genome, but only certain genes will be activated and making proteins in certain cells. This is how humans have different organs and cell types - the genes being 'expressed' and making proteins in liver cells (hepatocytes) will be different to those making proteins in brain cells (neurons).

Proteins consist of 'domains'. These domains are what allow proteins to do their work. Usually these domains give certain properties to a protein enabling them to interact with other proteins, move through certain places, and drive reactions needed in the cell. Proteins may can have multiple domains, with numbers depending on the function. The protein of ATP7B has 8 different domains - to bind its target, interact with targets and also for energy. It's a busy protein! 

ATPases like Copper-Transporting ATPase 2 are a class of protein that can take ATP (adenylpyrophosphatase) and utilise it as a source of energy. ATP is the energy molecule of a cell. A protein that can do this is able to use ATP to drive a reaction.  The P -type indicates that ATP7B is able to use phosphorylation to drive their action. ATPases are known as 'pumps' because they act as transporters and bind and move something throughout the cell. Often this action is across the cell wall. These types of pumps are found everywhere in the body and serve many important functions from nutrient uptake in the intestine,  controlling nervous impulses to secretion in the kidneys.

Copper-transporting ATPase 2  has a domain that binds to copper.
Copper-transporting ATPase 2  is also able to bind zinc, cadmium, gold and mercury but has the greatest affinity for copper.

Copper and other 'heavy metals' are needed in very tiny amounts in our cells for proper function. If they build up they become toxic and can damage cells, and left untreated this can result in death. Heavy metals can accumulate to toxic levels not only due to fault in the cell that means there are not removed but also due to too much exposure.  Each metal, like any element or chemical can be tolerated in different amounts, and the excess will impact on different organs in different ways. Too much copper results in damage to the mitochondria of the cell (aka. the power house of the cell that produces all the ATP), and as a result the cell dies.

Copper-transporting ATPase 2 is mostly found in an area of the cell called the Golgi Aparatus. At the Golgi, proteins being made undergo their final modifications so they are ready to undertake their function. It's the finish and polish station of the cell! Copper-transporting ATPase 2 adds copper groups to proteins that require it. If copper levels start exceeding normal levles, Copper-Transporting ATPase 2 will leave the Golgi and will act to transfer copper out of the cell through the vesicles. This copper then ends up in bile and is excreted. This protein is key in avoiding toxic buildup of copper in cells.

A defect in the sequence of ATP7B can result in Wilson's disease - that is, copper accumulation due to a genetic disorder. There are over 300 mutations known to occur in the gene however only a small number result in Wilson's disease. Some mutations in the genetic code of ATP7B can mean the protein produced doesn't function correctly. These mutations can be changes to single DNA bases,  deletions or frameshifts to the 3 base pair amino acid codes tat result in a different amino acid. The  mutations are inherited in an autosomal recessive way - the condition is found on the autosomes (non-sex chromosomes) and requires 2 copies of the defect to result in the disease. Note: copper accumulation and toxicity can occur for other reasons, Wilson's disease is specifically due to the mutations in the genetic code!

Wilson's disease is characterized by a number of symptoms that arise due to copper accumulation and the symptoms usually occur in the nervous system and liver. This includes vomiting, jaundice (yellowing skin and eyes), hallucinations ad muscle stiffness. A really striking feature and symptom of copper accumulation is the formation of Kayser-Fleischer rings on the eyes - see the picture below.

Kayser-Fleischer Ring on the eye (shown by arrow). Source: Wikipedia (CC)

To confirm Wilson's disease it must be determined whether it's a problem with ATP7B rather than another way that copper is accumulating. Diagnosis is through appearance of symptoms associated with copper accumulation, liver function tests, testing of serum and urine copper levels, MRI of the brain and genetic testing of ATP7B. A further test can be done for levels of ceruloplasmin, an enzyme that carries copper in the bloodstream. There actually isn't a definitive test for Wilson's disease itself, but rather a combination of  tests, and the gold standard - a liver biopsy can determine if Wilson's disease is the cause of the symptoms and the copper accumulation. Wilson's disease is not common - it occurs in approximately 1/30,000 people. Male and females are equally affected and it may occur anywhere between 5 and 35 years of age.

And if you are wondering, there is an ATP7A gene - it's produces a related, somewhat similar protein (57% homologous) that transports copper across the cell membrane to outside of the cell. Interestingly it's expressed everywhere in the body EXCEPT the liver. It's found on the X chromosome, so is in a completely different location and is sex-linked. 

So there you have it - our first stop on a tour of your genetic code - ATP7B.

More on ATP7B at OMIM 

More on the HGNCand human genes

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