BACH 2 is a protein that functions particularly within the cells of the immune system
to control precisely when certain genes are on and when they are off
as you can imagine when you have an infection it's the right thing to be able to respond
to it in the correct manner both in terms of how aggressive that response
should be and when it should be.
And BACH2 is one of those key proteins called transcription factors
that regulates some of that process and is very important, particularly for the
production of antibodies that fight infections
and for the biology of cells that prevent you from getting autoimmune diseases
where your immune system attacks yourself.
I think this is a very good example of how working collaboratively with colleagues
in different institutes and in different parts of the world
can result potentially in benefit for people.
And so we had a colleague in England who had found the first patient
We have a colleague in NIAID, Mike Lenardo who has a large database of patients
who have also have their genetic codes scanned and obviously we work within NIAMS.
And so together we sat down and looked through their database
and we found in fact that they did have patients with similar mutations in the same
gene that had a very similar medical history to
the patient in London.
That's how we all came together and decided to pursue this.
In the absence of BACH2 then, these patients had an absence of antibodies and also abnormal
responses against their own components, autoimmunity,
which is why we're calling it BRIDA Syndrome: BACH2-Related Immunodeficiency and Autoimmunity.
The two patient families had mutations in the BACH2 protein
and what we found was that the first protein mutation
is in this very important area which is required by BACH2
to stick to its' partner.
So BACH2 functions very much like a sandwich so the two pieces of bread have to bind and
stick to each other before it can carry out it's function.
Now what this mutation we discovered does is that it disrupts the glue between those
two, or if you like the butter that holds a sandwich
together.
So without that, the two pieces of bread fall apart
and they can't carry out their function.
The second mutation results in the protein actually forming
what can only be described as scrambled egg within the cell.
So it just sticks to itself and becomes a big ball of yarn
and stays outside of the nucleus where it would normally need to go.
So in both situations, you have less of the BACH2 protein
particularly in the area where it needs to function.
Now we all have two copies of each gene.
And what we have with BACH2 normally both copies
produce a certain amount of protein
But when one copy was mutated in these patients
the remaining protein wasn't enough
to keep the patients happy and without disease
this is a situation we call haploinsufficiency.
Now, if we imagined that you need a certain amount of this protein
and if we say that this protein is very important
then presumably it needs to be at the right level
at the right time.
So it needs to be on at the right time
and off at the right time and at the right levels.
These kind of proteins tend to therefore require
very tight regulation and so the area of the
genome that tells a protein when to be on and when
to be off is it's enhancer
Genes that have a very complex or large enhancer
have a structure we now call a superenhancer.
What we hypothesized was that genes that are similarly regulated
to BACH2 may share a common feature in causing disease.
That means that if you halve the amount of protein,
you're susceptible to getting disease and that is exactly what we found.
When a patient comes into hospital and we don't have an immediate answer for
why they may be ill it's relatively common these days to actually
scan their DNA to see whether they might have
a mutation in a gene that might be causing their disease.
The difficulty when you have this data is trying to pick out the gene that might
be responsible for that patient's disease.
It's relatively common practice to say initially that we will discount the genes in which
only one copy is abnormal or in which we might not obviously know
that that gene might be a cause of the disease.
The significance of these findings is that when patients come into hospital
and have their DNA scanned genes which have a superenhancer
and only one abnormal copy may actually be significant
in trying to determine whether
that might be the cause of the patient's disease.
Không có nhận xét nào:
Đăng nhận xét