In the last articles we briefly reviewed a
number of potential options to stop the activity of the fibroblast
growth factor receptor 3 (FGFR3) to block its effects in
the chondrocyte,
the cell responsible for creating the template where the bone will be built.
Due to the excessive activity of this receptor (remember, FGFR3 is a natural
brake controlling the bone growth pace), chondrocytes multiply (proliferate)
less than expected leading to an impaired bone development. The clinical result
is achondroplasia.
Besides blocking the receptor activity, there are other ways we can stop FGFR3
from exerting its actions. For instance, we can also block its production.
However, it is important to understand
that FGFR3 is not a villain. This receptor is part of a very complex program
that controls the bone growth. We would not like to simply abolish its
production, because this could also cause trouble. So, how to manage this
challenge?
FGFR3 production
Before reaching the cell
membrane, FGFR3 must be expressed (produced)
by the chondrocyte. Science is just beginning to unveil the complexity of the
chemical machinery that governs life, which includes understanding how the
genes are read and proteins are produced. Let´s talk a bit about this.
The human genetic code is organized in
chromosomes, chemical structures made of proteins and DNA that carry all genes.
We have two pairs of 23 chromosomes, and each chromosome of these pairs is
inherited from our parents (one from the mother, one from the father). This
also means that we earn each of the thousands of our genes in pairs, in the
same way. The following link will take you to an animation which shows how
chromosomes are organized. The end comes with a bonus, it will show you how
cells multiply (proliferate).
Now, we must remember the nature of achondroplasia. Achondroplasia is an autosomal
dominant genetic condition caused by a mutation in just one of the
two FGFR3 gene copies everyone has within the genetic code. In other words, in achondroplasia, instead of two similar copies of normal FGFR3 genes, the carrier has two
different copies, one of them with the normal composition and the other bearing
the nucleotide switch
(G1138A) which causes this condition. The altered gene rules over the normal
one (it is dominant). The dominance here is a result of the excessive activity
of the mutated protein, which in the jargon is called gain-in-function.
When the chondrocyte receives a specific
order (a chemical signal), it starts the process by which the FGFR3 genes
(both of them) will be read, allowing the production of the protein FGFR3 (the
normal and the mutated ones). Take a look in this animation, which shows
how a gene is read and the information required to the production of a protein
is obtained and processed.
The process by which a gene is read is
called transcription.
Basically, the gene made of DNA will be copied (transcribed) in the form of a
molecule made of RNA, which is called messenger RNA (mRNA).
The mRNA is driven out of the cell nucleus and taken to the ribosome in
the cytoplasm,
where it will be read, in a process called translation. Think in
the ribosome, a small cell organelle, as an assembly line. It will recognize
the sequence of nucleotides and create a chain of amino acids,
which will be chosen according to that sequence. Take a look to this article in
Wikipedia, which is a rich source of information about amino acids and how they
are organized to form proteins.
The whole process is incredibly complex
and this text and the animation I recommended above, although fits to explain
it, are also simplifications. Let´s see a bit more about the post-transcription
process, because here we have some opportunities where we can stop the mutated
FGFR3 to be produced. No pumped FGFR3, no bone growth arrest.
Getting into the cell nucleus
We are still far from knocking down a bad
gene directly in the DNA. Thus, we will not talk about correcting the mutation
itself. Although we cannot change the basic DNA code we can, for sure, modify
the result of it, although it is not a simple task.
The RNA world
We are going to explore a complex topic.
The text may seem sometimes quite arid. If this happens, try visiting the
references I am including in the text. They could explain in other ways the
processes we will be exploring, which in turn can help facilitate the
understanding.
During the last years, it has become increasingly evident that RNA is
much more than a ‘servant’ of the genetic code processing. Researchers
discovered that RNA has several other relevant distinct functions than being a
messenger of DNA, which includes the ability of regulating the progress of the
mRNA to protein translation. In other words, RNA, in one of the several formats
it can assume, can tell which gene will make a protein and which one not, a
very powerful function.
This ability of RNA has been called RNA
interference and several kinds of RNA molecules may interfere
in the protein production path. Before we continue, visit this link, sponsored
by Nature (the Journal), which will take you to a very illustrative (and
technical) animation which shows DNA transcription and also how the RNA
interference mechanism works.
Micro
RNAs
If you watched the video, you learned
about the micro
RNAs, or miRNAs (or miR n, where n is a
numeric code given to miRNAs). The miRNAs are small pieces of RNA that can
identify a sequence of nucleotides within a mRNA, binds to it and stop the
process of translation of the mRNA into a chain of amino acids (the future
protein). Many (hundreds) miRNAs have already been discovered and they play a
very relevant control function on protein expression (production).
The lack of a specific miRNA can lead to several diseases, because if a given
protein is released excessively the consequences may be harmful for the cell
(for instance, cancer). You can learn more about miRNAs reading this article in
Wikipedia.
In short, the mode of action of a miRNA is
as following: each miRNA has a sequence of nucleotides that is complementary (it
combines perfectly) to a sequence in the target mRNA. When a miRNA binds to a
mRNA, the messenger cannot be read anymore in the ribosome and is driven to
degradation and the protein is not produced anymore. The complementary nucleotide
sequence is short, so one property of the miRNAs is that although they are very
specific for the targets, there are several mRNAs bearing the same
complementary sequence and therefore are targets of the same miRNA.
For instance, the miR 99a can hinder
the FGFR3 mRNA
to be translated into the protein FGFR3. Could we use miR 99a to block FGFR3 in achondroplasia? The problem here is that miR 99a also blocks other protein expression,
such as of mTOR, which is a very important enzyme in cellular processes. When
the disease is cancer and both FGFR3 and mTOR are influencing the tumor growth,
it may be interesting to block these enzymes by a miRNA like miR 99a. However,
what would be the effect of this kind of action in a growing child? What about
the other enzymes else than FGFR3 being blocked by this controller miRNA? To
learn more about the tests made with the use of miRNA 99a in FGFR3, please
visit the Oncogene Journal website to read this paper published in March 2011.
In summary, we have briefly started to
learn about the existence of RNA molecules capable of controlling the
production of proteins. The first class of these RNA agents is represented by
the micro RNAs. At least one of them, miR 99a, could be theoretically used in
ACH to control FGFR3 production. However, unless there is an unique and
exclusive miRNA capable of identifying the mutated region of the FGFR3 mRNA
transcript and bind to it, giving miRNAs like the miR99a does not seem to be
the best strategy to treat achondroplasia. Micro RNAs maybe not the best tool,
but there are others.
We have just started to explore potential approaches to stop or reduce
the production of FGFR3 to treat the consequences of achondroplasia. RNA has
more to offer and we will look at another strategy that may help manage the
FGFR3 associated bone growth arrest in the next article.
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