Understanding Achondroplasia

Achondroplasia is the most common form of dwarfism, with a case estimate of ~1:15000 to 1:25000 births. In US, it is estimated that 200 hundred affected children are born yearly. Currently, in US and Western Europe there are estimates of about 25000 children affected.

Achondroplasia is caused by a single mutation (or error) in the sequence of the gene that encodes (carries the needed chemical information to produce) the protein known as fibroblast growth factor receptor type 3 (FGFR3). This error causes the expression (production) of an overactive FGFR3, which in turn leads to a significant reduction of the speed long bones grow.

But how does this speed reduction occur?

During childhood bones elongate through a very well organized process, in which a template made by cartilage is prepared followed by its substitution for bone tissue.

To allow an appropriate bone growth pace, the cells inside the cartilage growth plate, which we call chondrocytes, follow a very complex and controlled program, mastered by the presence, or absence, of dozens of distinct proteins and other compounds they produce or that arrive from the vicinity. The interaction of these molecules determines the rate of chondrocyte proliferation (multiplication) and their preparation to be substituted by bone cells (scientists call this event hypertrophy).

This system runs like a Mozart’s symphony: one protein (or molecule) interacts with others causing a cascade of cell events. Some of them will accelerate the proliferation or the hypertrophy and others will cause the opposite effect. When all instruments play in harmony we listen to a marvelous music piece, the bone grows normally. If one fails to keep the tone, it will be easy to perceive the music lost the magic. In the cartilage, the natural function of FGFR3 is to reduce the pace the chondrocytes proliferate. In achondroplasia, FGFR3 is playing too much. Because of this, chondrocytes can’t follow the planned program and the final result is that the affected person will not grow as much as he or she would be capable of.

Let’s see a bit more about the mutation. As you may remember, we carry two copies of all genes in our genetic code (DNA). An individual needs only one copy of the mutated FGFR3 gene to become affected by achondroplasia. This is what is called a ‘dominant’ mutation, the mutated gene rules over the normal one.

Genes are the guidelines for building proteins, the molecules that govern all aspects of life. They are made of determined sequences of four molecules called nucleotides (adenine, guanine, thymine and cytosine). Proteins are made of aminoacids placed in a sequence according to the information present within the genes. If the gene suffers a mutation, the protein is directly affected.

It is remarkable that the vast majority of people with achondroplasia has the same mutation in the FGFR3 gene: an adenine in the place of a guanine in the position 1138 of the gene sequence. When FGFR3 is produced, this change causes the substitution of one aminoacid, glycine, for an arginine in the position 380 of the protein chain.

Saying this way make it looks quite simple, but the consequence is not. With the arginine in the place of glycine, the protein adopts a different conformation (it ‘curves’ differently), thus exposing more certain parts of one of its ends that react more with other cellular molecules. As the natural action of FGFR3 is to reduce the car speed, if it works more efficiently it will tend to stop the car.

FGFR3 is not simply fluctuating within the cell like a fish to be caught. It has a known address, the chondrocyte cell membrane, where it is positioned in a way that one of its ends is located outside the cell and the other is inside it. So, we can understand FGFR3 as a kind of communication channel between the environment and the cell. The outside end of FGFR3 is like a port, though a specific port. It will allow only fibroblast growth factors (FGFs) to dock. It is when a FGF docks in the outside end that FGFR3 will exert its actions. The docking maneuver will lead to further modifications in the structure of the receptor and expose those active parts in its inside end, finally leading to a cascade of cell reactions, those that will impair the chondrocyte proliferation.

As depicted above, FGFR3 works in concert with other proteins. While FGFR3 is a brake within the growth plate cartilage, others work like accelerators. Two of these agents are worth of mention, because the actions they exert may give insights to one thinking in therapeutic solutions for achondroplasia.

The first one is the C-type Natriuretic Peptide (CNP). CNP is a natural positive player in the growth plate, influencing the expansion of the hypertrophic zone. It is released within the cartilage growth plate so exerts its effect locally. Studies demonstrated that it works by reducing the activation of some proteins in the FGFR3 cascade, so it partially counteracts the FGFR3 intracellular actions. Scientists have identified that mutations causing overactivation of the CNP receptor lead to overgrowth. Some slight changes in the same receptor are the proposed reason for the distinct higher final height of adults in certain countries of northern Europe.

The second one is a protein called Parathyroid Hormone related Protein, or PTHrP. As the name already states, it is a protein which keeps a high homology (similarity) with the hormone produced by the parathyroid glands (PTH). They also share the same cellular receptor, which means that as both molecules can bind to the same receptor they will likely cause the same cellular reactions. However, while PTH is working through the blood flow, PTHrP is a local molecule, acting within the growth plate. PTHrP main action is to keep chondrocytes proliferating, thus having the opposite effect of FGFR3. It is noteworthy that PTHrP works independently of the FGFR3 state (normal or mutated). When working excessively due to a mutation, the PTHrP receptor provokes another kind of very rare bone dysplasia, called Jansen’s Methaphyseal Chondrodysplasia (JMC). If PTHrP is absent, the bone growth will also be impaired.

There is already a lot of information here. Why are these so many details important? By identifying the mechanisms involved in the production of a protein, what is changed in it, where the active sites of that protein are and with which kind of other molecules it interacts, scientists can create molecules which could interfere with them, either blocking or activating these interactions. This is already happening, with hundreds of compounds available or being developed to beat mutated proteins in cancer and other diseases. In the case of achondroplasia, what we need is a compound capable of reducing of stopping the action of the mutated FGFR3 or able to counteract the mutation effects.

In the next post, we will start to look at the real world. What challenges we need to overcome, where the opportunities are. What is already on the table and what is waiting to be explored.