Advent Science Day Sixteen
Two case studies today, because examples really are the best way to teach this sort of thing.
The first is cystic fibrosis, which is the most common single-gene serious (ie, life-shortening) condition among people of European descent. CF is caused by a fault in a gene that codes for a protein that transports chloride ions across cell membranes, and is particularly interesting for this series because one missing amino acid (in the most common form of CF) can have such wide-ranging effects across the whole body. The most well-known symptom is that the natural mucus in the lungs forms too thick and sticky, making it hard to cough up and also a breeding ground for bacteria of various types. However, pretty much anywhere there is epithelium (surface cells) there are chloride ion channels, and this results in problems with things getting stuck in the digestive tract, low fertility (due to blocking of narrow tubes) and liver disease due to bile duct obstruction.
The *other* interesting thing about cystic fibrosis is that it varies greatly in severity. It's actually entirely possible for a mild version to remain undiagnosed until the patient is in their thirties and forties, and their body is no longer able to compensate as it did, or at least until fertility problems present themselves in adulthood.
And after the past couple of weeks, you should be able to understand how you can have a mild version of a single gene disease. While the most common cause of CF is a mutation in which one amino acid is deleted from the protein, rendering it completely non-functional, there are other known mutations in the same gene. Some of these produce protein that, as mentioned yesterday, works just about well enough that the patient can live a life relatively free of medical treatment, though may still struggle when exercising due to impaired lung function.
The other disease we'll take a brief look at is Huntington's Disease, because it's unusual in that it's actually a *dominant* gene that causes it. Huntington's is a neurodegenerative disease, and the reason that it is still so prevalent despite being a dominant gene is that, unlike most genetic disorders, the symptoms do not usually become noticeable until the patient is around forty years old, and therefore is quite likely to have already bred and passed on the gene.
So. How on earth do you get a dominant genetic disorder when we've already covered in detail how a recessive gene is a *lack* of normal protein? The reason lies in a loop region of the protein in question, which is called Huntingtin. This loop consists of a long chain of the amino acid glutamine, coded for by the sequence CAGCAGCAGCAGCAG etc etc. In people who do not suffer from Huntington's, this loop region is around 10-30 glutamines long. However, the longer this region is in the DNA, the more unstable is the replication machinery's bond to the DNA, and this can result in mutations that increase the number of CAG repeats present.
And when that number reaches a threshold of about 35 repeats, a misfolded version of huntingtin is produced, and it is that which causes the degeneration of the central nervous tissue over time. And it doesn't matter if you also have a copy of the gene that produces the functional protein- if you have any of the mutant form, you will eventually get the disease. Interestingly, though, the longer your glutamine repeat section is, the earlier in your life symptoms are likely to appear.
Tomorrow: You have probably heard about "carriers" of genetic diseases. We'll look at what that actually means, and (surprise surprise!) why it is not actually as simple as all that! Again!
The first is cystic fibrosis, which is the most common single-gene serious (ie, life-shortening) condition among people of European descent. CF is caused by a fault in a gene that codes for a protein that transports chloride ions across cell membranes, and is particularly interesting for this series because one missing amino acid (in the most common form of CF) can have such wide-ranging effects across the whole body. The most well-known symptom is that the natural mucus in the lungs forms too thick and sticky, making it hard to cough up and also a breeding ground for bacteria of various types. However, pretty much anywhere there is epithelium (surface cells) there are chloride ion channels, and this results in problems with things getting stuck in the digestive tract, low fertility (due to blocking of narrow tubes) and liver disease due to bile duct obstruction.
The *other* interesting thing about cystic fibrosis is that it varies greatly in severity. It's actually entirely possible for a mild version to remain undiagnosed until the patient is in their thirties and forties, and their body is no longer able to compensate as it did, or at least until fertility problems present themselves in adulthood.
And after the past couple of weeks, you should be able to understand how you can have a mild version of a single gene disease. While the most common cause of CF is a mutation in which one amino acid is deleted from the protein, rendering it completely non-functional, there are other known mutations in the same gene. Some of these produce protein that, as mentioned yesterday, works just about well enough that the patient can live a life relatively free of medical treatment, though may still struggle when exercising due to impaired lung function.
The other disease we'll take a brief look at is Huntington's Disease, because it's unusual in that it's actually a *dominant* gene that causes it. Huntington's is a neurodegenerative disease, and the reason that it is still so prevalent despite being a dominant gene is that, unlike most genetic disorders, the symptoms do not usually become noticeable until the patient is around forty years old, and therefore is quite likely to have already bred and passed on the gene.
So. How on earth do you get a dominant genetic disorder when we've already covered in detail how a recessive gene is a *lack* of normal protein? The reason lies in a loop region of the protein in question, which is called Huntingtin. This loop consists of a long chain of the amino acid glutamine, coded for by the sequence CAGCAGCAGCAGCAG etc etc. In people who do not suffer from Huntington's, this loop region is around 10-30 glutamines long. However, the longer this region is in the DNA, the more unstable is the replication machinery's bond to the DNA, and this can result in mutations that increase the number of CAG repeats present.
And when that number reaches a threshold of about 35 repeats, a misfolded version of huntingtin is produced, and it is that which causes the degeneration of the central nervous tissue over time. And it doesn't matter if you also have a copy of the gene that produces the functional protein- if you have any of the mutant form, you will eventually get the disease. Interestingly, though, the longer your glutamine repeat section is, the earlier in your life symptoms are likely to appear.
Tomorrow: You have probably heard about "carriers" of genetic diseases. We'll look at what that actually means, and (surprise surprise!) why it is not actually as simple as all that! Again!