The Causes of Clubfoot

Martin: -   At the moment, we're trying to solve the problem of what causes clubfoot.  It's a very common human condition and currently about 1 in 500 babies are being born in the UK with clubfoot.  We've very little idea about what's causing it.  There's a mixture of causes, probably some genetic, some environmental.  We're primarily looking at the genetic side of clubfoot, what predisposes people to be born with this condition.  The way we've been doing it is by looking at a strain of mouse that's been born with clubfoot for no apparent reason, but it's clearly a genetic condition that the mice are carrying which gives them clubfoot.  So we've been trying to look for the gene that causes clubfoot in these mice.

Chris: -   When you look at a person who has a clubfoot, what actually is wrong with them anatomically and what's wrong with these mice?

Martin: -   Well, what's wrong with people with clubfoot anatomically, you'd think it's a bone problem but most of the evidence is that really it's not.  It's more a muscular problem and it's the weakness of the lower leg muscles caused by - we don't know - anything.  Either a muscle atrophy, some sort of muscular disease, or where we're coming from the moment, a neuromuscular disease.  There's actually problems with the nerves and in particular, the branch of sciatic nerve that goes down the outer side of the leg, the peroneal nerve, appears to be defective.  It's certainly a problem in our mice model that they don't have their peroneal nerve.

Chris: -   Is it that the muscle is defective and that makes the nerve defective or the other way around?

Martin: -   Well this is an interesting question.  Clearly, from what we were seeing, the nerve is defective and because the nerve isn't firing, the muscle doesn't develop properly.  I don't think that is necessarily the case in all human clubfoot cases.  I think whatever you do to weaken those muscles can cause a clubfoot, so it can be a nervous effect or it can be a muscle effect.

Chris: -   Is it on both sides of the body usually, or do they usually just have one limb affected and one normal?

Martin: -   About half cases are bilateral - in both legs and in the other half, just one foot will be affected.  Slightly more common in males than females as well.

Chris: -   So not usual because if it's genetic, would you not expect it to be both legs?

Martin: -   This is one of the problems that we don't understand.  We can't conceptually think of one gene that's going to affect one foot but not the other.  We don't know of any changes in how genes are used between different legs.

Chris: -   So how are you trying to grapple with this problem?  We've got this mouse that develops something similar, how are you taking that forward?

Martin: -  Well, we're tracking the gene defect that's causing this problem in these mice. Then what we're going to do is have a collaborative effort with some clinicians, also at the University of Aberdeen, who've been collecting DNA from clubfoot patients for many years - they've got a huge bank of DNA samples - so the idea is that once we have the mouse gene, we'll go on and sequence all these human samples as well for mutations in the same gene.

Chris: -   How did you find the genes that might be involved?

Martin: -  By breeding mice that have the problem with mice that don't have the problem and then looking at all their babies and seeing which ones still have the problem.  We then check for bits of DNA from this mix of DNA that the mice with the problem are carrying.  So we just do lots and lots of genetic screening for different bits of all the chromosomes, all the DNA of the mice, and find which single little bit of DNA is carried with the genetic problem with this clubfoot every time.

Chris: -   And what does this gene do?

Martin: -   It appears to be controlling the nerves so we're getting a gene that's responsible for targeting the nerves to the right muscles and the outer side of the lower limbs in the legs.  Whether it's allowing those nerves to survive or whether it's telling it to go to the right place, whether it's targeting them correctly, that's the mechanism we're looking for.

Chris: -   It's interesting it's just the leg then, isn't it?

Martin: -   Yes and in human populations, it's extremely rare to find a club-hand.  There's one family in a forest in Northeast Scotland somewhere that has club-hands, but I mean, otherwise unless it's a degenerative arthritis type condition, there's nothing similar to clubfoot in newborn people in the hand.

Chris: -   So if you can work out how this gene is achieving this function, does that also mean there are potentially some spinoffs. How you can restore nerve or muscle interactions, how you can strengthen muscles, or regenerate nerves, and so on?

Martin: -   Clearly, there is yes.  Potentially, we may be able to repair the gene or give some sort of prenatal therapy.  The spinoffs are more likely to be in some other clinical areas because clubfoot is treatable and babies born with clubfoot can be casted. Most people recover and have a fairly normal life.  It's about 20% of cases where after the casting and manipulation, the foot just bounces back and these people need more complicated surgery.  We'd like to be able to identify those 20% of people and what it looks like is for people to have this nervous type of clubfoot that are suffering their relapses.  So finding the gene, we may be able to identify those people.  And also the gene that's causing the clubfoot in the mice.  It may or may not be responsible for more conditions in people.  There's a whole bunch of sensory, motor, neuropathies, degenerative disease in people that affects the lower legs that could be affected by this gene.