8.4 Fragile X syndrome
Fragile X syndrome is the final example of a genetic disease considered here.
What does the term ‘genetic disease’ mean?
Genetic disease means that the symptoms of the disease are associated with a particular allele. Note that the gene may be present, but it would be a faulty version, a faulty allele.
The term genetic disease also means that a protein is not present or is not doing its job properly. It is this alternative meaning that is important because it opens up the question of what the missing/faulty protein is failing to do; of what the function of the normal protein is.
The gene at the centre of fragile X syndrome is FMR1 (an abbreviation for fragile X mental retardation gene 1). The protein at the centre of fragile X syndrome is FMRP (fragile X mental retardation protein).
The symptoms of fragile X syndrome are numerous and varied. Some of the symptoms are physical, and include an elongated face, prominent large ears and a high arched palate. Others are developmental, meaning that certain motor patterns appear later than in unaffected individuals. These developmental symptoms include speech delay, fine and gross motor delay and coordination difficulties. There are behavioural symptoms too, including shyness, sensory defensiveness and mood instability. In addition, learning disability is a common symptom.
The large range of symptoms is due, in part, to two peculiar features of the disease which illustrate the intricacy of the relationship between genes and development. One feature has to do with the nature of the mutation and the complexity of DNA. The fragile X mutation is an addition; some DNA is added to the beginning of the FMR1 gene to create a new allele, and if enough DNA is added to the beginning of the gene, the extra DNA prevents the relevant transcription factor from starting transcription. The extra DNA prevents the allele from being transcribed. (The technical term for the addition of the DNA, which you need not remember, is a triplet repeat expansion.) While the embryo is a ball of dividing cells, in 10 per cent of individuals with the mutation, some cells carry an FMR1 allele which can still be transcribed. The upshot is that individuals with fragile X syndrome can have a mosaic of two types of cells, those transcribing and those not transcribing FMR1. As a result, the symptoms can differ between individuals depending on which cells can transcribe FRM1.
The second peculiar feature has to do with the function of the protein product of FMR1, FMRP. The end product of transcription is messenger RNA (mRNA). mRNA leaves the nucleus before being translated into protein. To leave the nucleus, mRNA must pass through the nuclear membrane, and as you know, membranes are designed to prevent things passing through them. Just as ions need the assistance of protein channels to pass through the cell membrane, so mRNA needs the assistance of protein transporters to pass through the nuclear membrane. To keep cell biologists in work, nature has arranged things so that there are numerous mRNA transporter proteins, each transporter protein assisting only a select group of mRNA molecules out of the nucleus and transporting them for translation. FMRP is involved with regulating the transport and translation of some mRNAs. What this paragraph means is that those select mRNAs which happen to find themselves in cells without FMRP, cannot leave the nucleus.
What is the immediate consequence of mRNA failing to leave the nucleus?
The protein for which the mRNA codes cannot be made.
What these three examples illustrate is that genetic diseases vary enormously in their consequences, i.e. whether they are congenital, lethal, treatable, pleiotropic or what the symptoms might be. Labelling a disease as genetic rules out other potential causes of the disease, such as viruses, bacteria, pathogens and poisons. The medical profession rightly seeks to distinguish between these causes, to allow attention to be focused on the appropriate management and treatment of the disease.
The final section in this chapter considers an example where the quest for a genetic correlate is applied to a psychological problem.