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Science/Tech See other Science/Tech Articles Title: Small genetic mutation, big problem Think of the human genome as a book: a chromosome represents a chapter, a gene a sentence, a nucleotide a letter. It’s difficult to fathom that one small typo - a T replaced with an A, for instance - could obscure the meaning of an entire sentence. But this is precisely the cause of many genetic diseases. ANU PhD student Stephen Fairweather works on one such disease, Hartnup disorder, which is characterised by symptoms such as extreme sensitivity to sunlight, unsteady walking and mental disorder. These diverse symptoms are the result of a single letter change, or ‘mutation’, which prevents the body from absorbing the building blocks of proteins (amino acids) during digestion. Here’s how a little mutation can cause big problems. A gene called B0AT1 stores the information needed to build a protein of the same name. The B0AT1 protein is a type of protein known as a ‘transporter’. It sits on the membrane of the cells lining your gut and acts as a courier van, ferrying amino acids from your food into the cells of your intestine and kidney where they can be used to build important proteins which keep your body running smoothly. But, when the B0AT1 gene is mutated, the instructions for building the B0AT1 protein become garbled and the finished product is unable to transport amino acids. “There are two different types of mutation that can stop B0AT1 from working,” Stephen explains. The first type of mutation makes B0AT1 unable to ferry amino acids across the membrane. “If you imagine B0AT1 as a van, it would be like removing a part of the motor so that it can’t function,” he says. The second type of mutation prevents B0AT1 from interacting with other proteins that help it to travel, or ‘traffick’, to the cell membrane. “In this case B0AT1 itself might still be working but it can’t get to where it needs to be,” Stephen says. Stephen’s work focuses on the second type of mutation. Under the supervision of Professor Stefan Bröer, he is looking at how B0AT1 interacts with two other proteins, ACE2 and APN. The everyday job of ACE2 and APN is to break down proteins from food into single amino acids that can be transported into the cells of your gut by B0AT1 and other proteins like it. However, Stephen has discovered that ACE2 and APN have a few other tricks to their trade. He has found that ACE2 and APN act like police escorts, shepherding B0AT1 as quickly and safely as possible along the highway connecting where it is built in the endoplasmic reticulum to where it needs to be on the cell membrane. “I have also discovered that they interact with B0AT1 at the membrane to help it transport amino acids more efficiently,” he says. “We have strong evidence that all three of these proteins sit together in clusters on the membrane and function together as a single unit. Just like a production line, the closer things are to one another, the more efficiently they can work,” he says. Stephen thinks understanding the interactions between these proteins may lead to solutions for diet-related health conditions, such as obesity and malnutrition. “What we really want to know is how amino acid absorption is regulated at different times,” he says. “For example, if you’ve had a big meal, the body might minimise amino acid absorption by regulating these proteins.” “The question is: could we somehow control the regulation of these proteins to enhance amino acid absorption when dietary protein is scarce or vice versa in western countries where people eat a lot of protein?”
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