Science Q & A !!!

Q: Something that has been on my mind for some time now and I hope that you will know where to look for an answer. Why do children with Fragile X exhibit a consistent phenotype, large ears, etc.? You will already have thought about this, I am sure. I just can't understand why a single protein deficiency would influence the general development of a human. Does it happen also with the mice? Does the fragile X mouse model exhibit similar phenotypic appearances? If not, then I would start to wonder if the model was accurate, wouldn't you?

A: Of course, we don't know all the details yet, but a few key answers to this question have come from the research. First of all, it is known (especially from drosophila work) that the normal role of FMRP, as an RNA-binding protein, is to help regulate directional growth in most (if not all) cells. This can be seen in fly oocytes, where normal anatomy is severely disrupted by mutations of dFMRP; fertility is also impaired, though this still does not result in sterility (which is very good luck for us, or we'd have no fly model of fragile X.) So, from this perspective we can see that this mutation would cause the greatest disruption in the most spatially differentiated cells: neurons. Other cells are affected, though, and that may explain some of the dysmorphic physical features.

The mice do have some physical phenotype, but I think it's just hard for us, as a different species, to recognize. Human facial recognition is very highly evolved; I doubt that the mice would be able to tell any difference in our faces! They certainly do have larger testes; no one has looked at their connective tissue, but I'm sure it's quite lax (just hard to examine or quantify this.)

Beyond direct effects on directional cell growth, there are the many known indirect effects, for example on hormone regulation. We know from Carolyn Beebe Smith's work at NIMH that protein synthesis is dysregulated in much of the fragile X brain, but the hottest of all the hot spots for excessive protein synthesis is the hypothalamus, with about 32% more activity in fraX vs. normal. That is a huge difference for a whole brain region! The hypothalamus is responsible for regulating a wide range of hormones in the body, and these, in turn, regulate cell growth in a number of ways. Because of the elaborate control mechanisms in the body, with multiple feedback loops, we don't see vast increases in one hormone or another at any one time in fragile X people, but we really haven't looked very hard, either. What is likely happening is that the fine regulation of hormonal response is lost. For example, Alan Reiss showed abnormal response of cortisol to social stress---but the cortisol levels weren't crazy-high, they were just a bit more prolonged than normal. Likewise, many of the facial features are reminiscent of acromegaly, though high levels of growth hormone have not been shown in humans or mice. It may be a more subtle defect than that. Interestingly, Abdeslem El-Idrissi at CUNY Staten Island has found low levels of somatostatin (in some ways, the opposite of growth hormone) in the knockout mouse; this could explain many features of fragile X, and is potentially treatable (somatostatin can be administered via injection, and synthetic analogs are being developed with oral bioavailability).

On a finer level, the excess in activated MMP-9 in fragile X, which was found in the mouse model by Iryna Ethell, could explain many of the CNS and non-CNS phenotypes seen in fragile X. This extracellular enzyme is part of a large and complex system which regulates the stiffness of the extracellular matrix---the foundation for all cell growth. We know that MMP-9 activity can be regulated through mGluR5 (at least in neurons) and that mGluR5 is present on many non-neuronal cell types. Of course, we can block MMP-9 activity directly with minocycline, but the evidence suggests that mGluR5 antagonists could also help with this problem, certainly in neurons, but probably in a great many other cell types as well. I certainly never expected that we would come up with treatments for the physical features of fragile X (and we weren't really looking for this) but it's quite promising. The experience with minocycline suggests that we can fix the lax connective tissue with this drug, and the research suggests that mGluR5 antagonists could work, too. Since most kids with fragile X (at least in the future) will be treated with these drugs well before the majority of physical development, this may modify the phenotype significantly. Time will tell if these findings hold up, or if the story is more complicated/less amenable to treatment.