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Actin gene causes congenital myopathy -

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Actin gene causes congenital myopathy

Congenital myopathy covers a range of rare lethal diseases. They affect muscle fibres. Babies born
with congenital myopathy are often born paralysed. Kristen Nowak and Nigel Laing at the University
of Western Australia traced mutations in the actin gene as the cause. They describe how the project
began and how their work has produced results which may lead to a cure.

Transcript

Robyn Williams: The floppy baby story also began in South Australia. It's a story about genes and
babies and long-term detective work. Meet Kristen Nowak and Professor Nigel Laing from the
University of Western Australia.

Nigel Laing: Our work with this group of diseases, the congenital myopathies, actually started with
a large family from South Australia. The real beginning of all this was walking down Alice Spring's
high street with Eric Haan who is the chief clinical geneticist in South Australia, and he said,
'Nigel, we have this family in South Australia with ten living affected people. Are you interested
in working with this family?' And of course ten is the magic number, and that family was big enough
to track down. So that's where we started from. And in 1995 we tracked that gene down to being a
mutation in tropomyosin which is one of the proteins of the thin filament in your muscle fibres.

Robyn Williams: Okay, so it affects muscle. In what way?

Nigel Laing: Children are born affected, and in the most severe form they can be born almost
completely paralysed. And then there is a spectrum of severity through to adult forms. So nemaline
myopathy can come on at any time from in utero to being an adult. It was always known that it was
genetic and the question was how to track down the genes, and that first big family from South
Australia basically unlocked the disease.

Robyn Williams: How did the family respond to being under your microscope?

Nigel Laing: The family was very keen to be involved and it all went very smoothly.

Robyn Williams: With these genetic clues, Kristen, how did you get involved?

Kristen Nowak: I started with Nigel doing some work experience and he was brave enough to take me
on as a research assistant to start with, and I found that he was so dedicated to the families that
we were researching. We were studying DNA samples from patients and families all around the world.

Robyn Williams: When you say 'work experience', do you mean when you were at school, you were just
wanting to know what it was like in a lab?

Kristen Nowak: No, I actually had already graduated, I'd done my bachelor of biotechnology and then
honours. But I do remember thinking about DNA and finding it really exciting at school. So I can
remember one of my year ten teachers telling us about her family, she had about six or seven
siblings, and she had a lethal form of dwarfism in her family, and I remember her then telling us
that they could track down what was causing that disease with DNA.

Robyn Williams: You became a tracker. What did you do?

Kristen Nowak: Nigel had met a professor from Germany, Hans Goebel, who's a leading expert in
neuropathology, and he had presented three patients, unrelated, who had this unusual form of
pathology in their muscles, and two of them were very severely affected and they had died within
the first few months of life. Nigel had looked at that and said it looks like there's aggregates of
actin, which is one of the fundamental proteins of making your muscles contract. It looks like
there's a lot of this protein aggregating in this muscle. Perhaps one of the genes that's involved
with this disease is actin itself.

Over a period of probably six to 12 months, DNA samples from these samples were sent to us here in
Perth and we were able to study the DNA, and we found the first mutation in this gene called actin,
and that was the first time anyone had found mutation in that gene. And then we ended up finding
three different mutations in these three patients, and it started from there.

Nigel Laing: What was showed was that frequently because it's a lethal disease, the affected
children have new mutations not present in either of their parents. So the mutation has arisen de
novo in either the sperm or the egg that give rise to them, and that's a clue that that's what's
causing the disease.

Robyn Williams: Why should it happen like that?

Nigel Laing: The way I think about that is every time our cells divide you basically have to type
out (I worked it out one time) 17 years of non-stop typing, and no biological system is that
accurate. So every time our cells divide we get new mutations and it's just fate.

Robyn Williams: It's like the difference between the word 'fist' and 'fish'. Fists and fishes are
quite different, and that's only four letters, so a mistake like that on a gigantic scale, you're
bound to get some sort of error. The latest paper isolates it down to this particular gene. In what
way has the latest paper refined things?

Nigel Laing: One of the things that we hypothesised was that those are the mutations in the actin
of your skeletal muscles, and we always knew that there's also another actin gene which is for your
heart, and that actin is also the foetal actin in our muscles. So it's expressed in our skeletal
muscles before we are born, and then for reasons that nobody knows, it's switched off around about
the time of birth. And so we thought that one way you might be able to treat the skeletal actin
diseases was with cardiac actin.

And then we found another group of patients who have no skeletal actin in their muscles, and what
we found were a number of patients who had no skeletal actin in their muscles at all. When we first
did the analysis of the gene and found those mutations I thought this couldn't be true because the
clinical picture of some of these patients was not as severe as some of the patients with the
dominant actin mutations. And so what's the answer? The answer is those patients with the recessive
absence of skeletal actin have themselves kept their foetal form of cardiac actin going. And so
they're existing on having cardiac actin in their skeletal muscles, which isn't normally there.

Robyn Williams: They have another supply.

Nigel Laing: Yes. But we found those after Kristen started doing the mouse work, so what we set off
to do with the mouse work was to see to what extent cardiac actin could replace skeletal actin in
the skeletal muscles.

Kristen Nowak: Yes, so we've done that, and we were able to make some transgenic mice that kept
their cardiac actin switched on after birth as well as their skeletal muscle actin. We didn't know
whether that itself would be deleterious because maybe nature had made cardiac actin be switched
off for a reason. And then we also imported some mice from Cincinnati; Professor Jim Lessard made
some mice which were like these patients Nigel was telling you about which had no skeletal actin.
These mice die about nine days after birth, and we think it's the cardiac actin that's there during
development that keeps them alive, and then once that switches off and the skeletal actin is
supposed to switch on at birth, it's not there to do so. So unfortunately they die.

We're able to breed these mice together, so we created mice that didn't have the skeletal actin but
instead they had the cardiac actin in their skeletal muscle after birth. We were hoping that they
would live a little bit longer than nine days, and in fact they did and they're still alive now
after two years of age. And that's another time when Nigel didn't believe the results and he made
us repeat it many times, and they were running around just like their controls who were normal.

But the exciting thing is that we've found not only are these mice surviving and they seem to be
running around and doing quite well, but they actually do better than normal mice. So we've found
that they can run about 2.5 times further than mice usually do (this is kilometres per day) and
they also are more active. And what's interesting as well, we're not sure if it's because of all
their running, but they have less visceral fat, they have less fat around their kidneys and their
reproductive organs, about three times less fat. So that's something that was quite unexpected.

Robyn Williams: It's amazing. But one thing that puzzles me, if this actin, this material, which is
essential for the working of your muscle, is there separately in a system for the heart, why
doesn't it stay in the heart? How does it get to the skeletal muscles and your biceps and legs and
all that sort of thing? Why isn't it just confined to the heart?

Kristen Nowak: What we've done is we used a skeletal muscle specific promoter to activate it in the
skeletal muscles as well. So it's there in the heart and it's now in these mice there in the
skeletal muscle also.

Robyn Williams: So because all those cells have got the same sets of genes, you can switch on the
heart material?

Nigel Laing: We've genetically engineered the mice so that they'll express the heart actin in the
skeletal muscles. So these are genetically modified mice. So these aren't just normal mice where
we've managed to activate the heart gene in skeletal muscles, but that's the next step that we
would have to go through to try and treat the actual human patients because you cannot make
genetically modified people.

Robyn Williams: Not yet anyway!

Nigel Laing: No. The ultimate prize with this work is to try and find some way in the patients of
keeping their cardiac actin gene going in their skeletal muscles after they normally switch it off
or getting it switched back on again.

Robyn Williams: If you crack the puzzle, how many potential patients are we talking about around
the world?

Nigel Laing: These are rare diseases. As far as rare diseases are concerned, one of my readers in
the University of Edinburgh said something once which was that if you've got the rarest disease in
the world, it's the most important disease to you. And that has stuck with me, as someone who works
in a group of rare diseases. But these are nasty, nasty diseases. As I said, the most severe forms
of these, which a lot of the patients who have actin mutations have, they're born almost totally
paralysed and they go into ventilators straight away. And couples who've had a child like this do
not want to have another child, and so tracking the gene down and making prenatal diagnosis
available all around the world has been a huge thing for these families.

Robyn Williams: Professor Nigel Laing at the University of Western Australia, with Dr Kristen
Nowak, and a good article on their achievement is in the current edition of Australasian Science
magazine. Saving babies with useless body muscles by growing them heart muscle substitutes instead.
Clever stuff.