Searching for new genes that cause periodic paralysis and the myotonias
Up to a third of patients with periodic paralysis or myotonia do not have a genetic diagnosis. In this project Professor Hanna and his PhD student at University College London will search for new genes causing these conditions. They will also try to establish why two individuals with the same genetic fault can be affected with different severities. This project will allow patients to be given more accurate information about their condition and will contribute to the development of treatments in the future.
Contents:
- What are the researchers aiming to do?
- How will the outcomes of the research benefit patients?
- Background information
- Grant information
- Further information and links
What are the researchers aiming to do?
The channelopathies is an umbrella term for a group of conditions that includes periodic paralysis, myotonia congenita and paramyotonia congenita. They are all caused by faults in genes that code for ion channels - pores in the walls of muscle cells that allow the flow of molecules such as potassium and sodium into and out of muscle cells. Ion channels are vitally important for a whole range of functions including muscle contraction and relaxation. When there are problems with particular types of ion channels people can experience episodes of muscle stiffness and/or paralysis.
Although faults in several genes are known to be involved in causing the channelopathies, there is a group of patients who have yet to be given a genetic diagnosis. These individuals do not appear to have a fault in any of the known genes. Prof Hanna and his student will examine the DNA from this group of individuals, initially looking at a set of genes suspected to be involved in the functioning of ion channels. If nothing arises they will continue to examine other genes that are active in the muscle.
The channelopathies are a variable set of conditions ranging from mild to very severe. Symptoms can vary between individuals even between two people who carry the same genetic fault. The conditions that Prof Hanna is studying are inherited in an autosomal dominant manner. Everyone inherits two copies of every gene, one copy from each parent. If a disease is autosomal dominant this means that you only need to inherit one faulty copy of the gene to have the disease. Prof Hanna believes that in the channelopathies the "healthy" gene and the "faulty" gene are both active in the cell and so the relative contribution of each gene could affect how severe the symptoms are.
When the cell needs to produce a protein, the instructions in the DNA are read and a new messenger molecule is created. This messenger molecule, called mRNA, will carry the instructions out of the nucleus where the DNA is located to the main body of the cell where the proteins are produced. Since everyone has two copies of each gene, the mRNA could be carrying the instructions from either copy. The cell will not necessarily use 50% of instructions from one gene and 50% from the other. It may be that one gene is contributing more sets of instructions, and this is what Prof Hanna will be looking at in these patients. Prof Hanna will measure how much of the "healthy" genetic code is being sent to the protein producing machinery and how much of the "faulty" code is being used. This will allow them to study whether individuals in whom there is a greater amount of the "faulty" genetic code being used have a more severe condition. In addition they will also investigate, using fluorescent dyes, whether the ion channels are being placed in the wrong location in the cell - something that can prevent the channels from functioning correctly.
How will the outcomes of the research benefit patients?
This research will benefit patients in a number of ways. Firstly, uncovering new genes that may be involved in the channelopathies will allow a greater number of patients to benefit from a genetic diagnosis. Having an accurate genetic diagnosis allows individuals and families to better plan for the future since clinicians will be able to give them a more accurate picture of how their condition is likely to progress.
This work could also provide vital information about the underlying cause of the channelopathies. Knowing more about what causes a disease is important to give researchers targets to focus on in the development of new treatments for these conditions. Understanding the basis of the variability of the condition is also useful for clinical trials. It is important to have groups of individuals who are as similar as possible in order to be able to properly measure the effect of the drug being trialled. By understanding what causes the variation, then this can be minimised during the trial design.
Background information
In the last 20 years, genes for many of the muscle conditions have been discovered. This has lead to accurate diagnosis and genetic counselling for these conditions. There are still cases where the gene has not yet been found and it can be very difficult for scientists to narrow down exactly which one could be causing a disease.
Finding a mutation that could be causing a disease can be a long and complicated task. Scientists need to look for clues to give them a starting point. One such starting point is to compare the DNA of family members affected by a condition to those not affected. If there is an area of DNA that is always different in the affected individuals compared to the non-affected individuals then it is likely that the gene they are looking for is in this area. Further investigation and testing of that area of DNA may reveal the location of the mutated gene.
A second approach, which Prof Hanna and his student will be using, involves examining specific candidate genes that have been chosen based on their function and role in the cell. For instance, it is know that the channelopathies are generally caused by a fault in the gene that carries the instructions for an ion channel. Researchers might, therefore, chose to study other genes that carry the instructions for ion channels, proteins that are very similar to ion channels or proteins that might be associated with or interact with the ion channels. If they find a change in any of these genes, further tests are then needed to determine if it is a disease-causing mutation or simply a natural variation in the genetic code.
Grant information
Project leader: Prof Michael Hanna
Location: University College London
Conditions: Channelopathies (periodic paralysis, myotonia congenita and paramyotonia congenita)
Duration: 4 years
Total project cost: £121,156
Official title: Genetic heterogeneity and mechanisms of phenotypic variability in human skeletal muscle channelopathies
Further information and links
Learn more about the myotonias.
Learn more about periodic paralysis.
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