This results in a strange phenomenon where junk RNA is changed to protein-coding RNA. This adds an extra five amino acids to the start of the normal protein, as shown in Figure 16.3. The protein involved in this type of brittle bone disease is one that has parts inside and outside the cell. The alteration in the junk DNA adds an extra five amino acids to a part of the protein that is outside the cell.
It’s not quite clear why these five amino acids cause the symptoms of the disease. Previous experiments in rodents had shown that too much or too little of this protein leads to defects in the skeleton, so it’s clear that having exactly the right amount of the protein is important.{312} The extra five amino acids are on a part of the protein that we would expect might bind to other proteins or molecules that signal to the bone cells. It may be that having these extra five amino acids stops the mutant protein from responding properly, like putting chewing gum on the sensor of a smoke detector.
Figure 16.2 A mutation in the untranslated junk region at the beginning of the messenger RNA mis-directs the ribosome. The ribosome begins sticking amino acids together too early, creating a protein with an extraneous sequence at the beginning.
Figure 16.3 The U-shaped protein on the right has an extra five amino acids at the beginning, represented by stars. These extra amino acids probably influence which other molecules can interact with this protein.
Brittle bone disease isn’t the only human disorder caused by mutations in the untranslated regions at the start of a gene. There is a strong genetic component in about 10 per cent of cases of melanoma, the aggressive skin cancer. A mutation has been identified in some of these genetically driven cases that works in a very similar way to the problem in brittle bone disease. Essentially, a single base change in the untranslated region at the start of a gene creates an abnormal AUG signal in the messenger RNA. This again results in the ribosome starting the amino acid chain too early in the gene sequence. This creates a protein with extra amino acids at the start, which behaves in an abnormal way, increasing the chances of cancer.{313}
As always, we need to beware of seeing patterns from too little data. Not all mutations in the untranslated region at the start of a gene create new amino acid sequences. There is another type of skin cancer which is usually much less aggressive than melanoma. This is called basal cell carcinoma, and it too has a strong genetic component. A rare mutation was found in a father and his daughter, both of whom developed this kind of tumour.
The untranslated region at the start of a particular gene usually contains the sequence CGG, repeated seven times, one after the other. The affected father and child had an extra copy of the CGG. Having eight repeats rather than seven predisposed them to basal cell carcinomas. This mutation didn’t change the amino acid sequence of the protein encoded by the gene. Instead, the extra three bases seemed to change the way the messenger RNA was handled by the ribosome, in ways that aren’t very clear. The end result was that the cells of the patients expressed much less of the specific protein than normal.{314}
Cancer is a multi-step disease, and although these mutations in the untranslated region at the start of certain genes predisposed the patients to tumours, other events probably also took place in the cells before full-blown cancer developed.
But we have already encountered a disorder where an inherited mutation in the untranslated region at the start of a gene leads directly to pathology. This is the Fragile X syndrome of mental retardation (see page 19). As a reminder, the mutation is an unusual one. A three-base-pair sequence of CCG is repeated far more times than it should be. Anything up to 50 copies of this repeat is considered to be in the normal range. Fifty to 200 copies is not normally associated with disease, but once the number of repeats gets into this range it becomes very unstable. The machinery that copies DNA for cell division seems to have trouble keeping count of the number of repeats, and even more repeats get added. If this happens in the gametes, the resulting child may have many hundreds or even thousands of the repeats in their gene, and they present with the Fragile X syndrome.{315}
The longer the repeat, the lower the expression of the Fragile X gene. As we saw in an earlier chapter, this is because of cross-talk with the epigenetic system (see page 123). Where C is followed by G in our genome, the C can have a small modification added to it. This is most likely to happen in regions where this CG motif is present at high concentrations. The large number of CCG repeats in the Fragile X expansion provide exactly this environment. The untranslated region in front of the Fragile X region becomes very highly modified in the patients, and this switches the gene off. Fragile X patients don’t produce any messenger RNA from this gene, and consequently don’t produce any protein from it either.
The effects on the patient of this lack of protein are dramatic. Patients are intellectually disabled but also have symptoms reminiscent of some aspects of autism, including problems with social interactions. Some patients are hyperactive, and some suffer from seizures.
This of course makes us wonder what the protein normally does. The clinical presentation is quite complex, which suggests that the protein is probably involved in complicated pathways, and this indeed seems to be the case.
As we saw in Chapter 2, the Fragile X protein is usually complexed with RNA molecules in the brain. The protein targets about 4 per cent of the messenger RNA molecules expressed by the neurons.{316} When it binds these messenger RNA molecules, the Fragile X protein acts as a brake on their translation into proteins. It prevents the ribosomes from producing too many protein molecules from the messenger RNA information.{317}
This extra level of control on gene expression seems to be particularly important in the brain. The brain is an extraordinarily complex organ, and the cell type that is of most interest to us is the neuron. This is what people usually mean when they talk about brain cells. There are an awful lot of neurons in the human brain, the most recent estimate being just over 85 billion.{318} Each brain contains twelve times as many neurons as there are people on earth. And in the same way that people have complex networks of friends, acquaintances, lovers, families and enemies, neurons are also linked in. What’s startling is the degree of connection between the billions of neurons. Neurons send out projections that connect with other neurons in vast networks, constantly influencing each other’s responses and activities. The precise number of connections is really difficult to estimate, but each cell probably makes at least 1,000 connections with other neurons, meaning our brains contain at least 85 trillion different contact points.{319} It makes Facebook look positively parochial.
Establishing these contacts appropriately is a huge task in the brain. Think of it as arranging to see good friends frequently while trying to avoid the weird guy you met in your first week at college. Contacts are set up and then either strengthened or pruned back, in complex responses to environment and to activities of other neurons in the network. Many of the target messenger RNAs that bind to the Fragile X protein under normal conditions are involved in maintaining the plasticity of the neurons, allowing them to strengthen and prune connections as appropriate.{320} If the Fragile X protein isn’t expressed, the target messenger RNAs are translated into protein too efficiently. This messes up the normal plasticity of the neurons, leading to the neurological problems seen in the patients.