Females with a mutation in the same gene are usually perfectly healthy. LYSOSOMAL IDURONATE-2-SULFATASE protein is usually secreted out of the cell that makes it and taken up by neighbouring cells. In this situation it doesn’t matter too much which X chromosome has been mutated in a specific cell. For every cell that has inactivated the X carrying the normal version of the gene, there is likely to be another cell nearby which inactivated the other X chromosome and is secreting the protein. This way, all cells end up with sufficient LYSOSOMAL IDURONATE-2-SULFATASE protein, whether they produce it themselves or not[116].
Duchenne muscular dystrophy is a severe muscle wasting disease caused by mutations in the X-linked DYSTROPHIN gene. This is a large gene that encodes a big protein which acts as an essential shock absorber in muscle fibres. Boys carrying certain mutations in DYSTROPHIN suffer major muscle loss that usually results in death in the teenage years. Females with the same mutation are usually symptom-free. The reason for this is that muscle has a very unusual structure. It is called a syncytial tissue, which means that lots of individual cells fuse and operate almost like one giant cell, but with lots of discrete nuclei. This is why most females with a DYSTROPHIN mutation are symptom-free. There is enough normal DYSTROPHIN protein encoded by the nuclei that switched off the mutated DYSTROPHIN gene to keep this syncytial tissue functioning healthily[117].
There are occasional cases where this system breaks down. There was a case of female monozygotic twins where one twin was severely affected by Duchenne muscular dystrophy and the other was healthy[118]. In the affected twin, the X inactivation had become skewed. Early in tissue differentiation the majority of her cells that would give rise to muscle happened, by ill chance, to switch off the X chromosome carrying the normal copy of the DYSTROPHIN gene. Thus, most of the muscle tissue in this woman only expressed the mutated version of DYSTROPHIN, and she developed severe muscle wasting. This could be considered the ultimate demonstration of the power of a random epigenetic event. Two identical individuals, each with two apparently identical X chromosomes, had a completely discordant phenotype, because of a shift in the epigenetic balance of power.
Sometimes, however, it is essential that individual cells express the correct amount of a protein. You may have noticed in Chapter 4 that Rett syndrome only affected girls. One might hypothesise that boys are somehow very resistant to the effects of the MeCP2 mutation, but actually the opposite is true. MeCP2 is carried on the X chromosome so a male foetus that inherits a Rett syndrome mutation in this gene has no means of expressing normal MeCP2 protein. A complete lack of normal MeCP2 expression is generally lethal in early development, and that’s why very few boys are born with Rett syndrome. Girls have two copies of the MeCP2 gene, one on each X chromosome. In any given cell, there is a 50 per cent chance that the cell will inactivate the X that carries the unmutated MeCP2 gene and that the cell will not express normal MeCP2 protein. Although a female foetus can develop, there are ultimately major effects on normal post-natal brain development and function when a substantial number of neurons lack MeCP2 protein.
There are other issues that can develop around the X chromosome. One of the questions we need to answer about X inactivation, is how good mammalian cells are at counting. In 2004 Peter Gordon of Columbia University in New York reported on his studies on the Piraha tribe in an isolated region of Brazil. This tribe had numbers for one and two. Everything beyond two was described by a word roughly equating to ‘many’[119]. Are our cells the same, or can they count above two? If a nucleus contains more than two X chromosomes, can the X inactivation machinery recognise this, and deal with the consequences? Various studies have shown that it can. Essentially, no matter how many X chromosomes (or more strictly speaking X Inactivation Centres) are present in a nucleus, the cell can count them and then inactivate multiple X chromosomes until there is only one remaining active.
This is the reason why abnormal numbers of X chromosomes are relatively frequent in humans, in contrast to abnormalities in the number of autosomes. The commonest examples are shown in Table 9.1.
Table 9.1 Summary of the major characteristics of the commonest abnormalities in sex chromosome number in humans.
The infertility that is a feature of all these disorders is in part due to problems when creating eggs or sperm, where it’s important that chromosomes line up in their pairs. If there is an uneven total number of sex chromosomes this stage goes wrong and formation of gametes is severely compromised.
Leaving aside the infertility, there are two obvious conclusions we can draw from this table. The first is that the phenotypes are all relatively mild compared with, for example, trisomy of chromosome 21 (Down’s syndrome). This suggests that cells can tolerate having too many or too few copies of the X chromosome much better than having extra copies of an autosome. But the other obvious conclusion is that an abnormal number of X chromosomes does indeed have some effects on phenotype.
Why should this be? After all, X inactivation ensures that no matter how many X chromosomes are present, all bar one get inactivated early in development. But if this was the end of the story there would be no difference in phenotype between 45, X females compared with 47, XXX females or with the normal 46, XX female constitution. Similarly, males with the normal 46, XY karyotype should be phenotypically identical to males with the 47, XXY karyotype. In all of these cases there should be only one active X chromosome in the cells.
One thought as to why people with these karyotypes were clinically different was that maybe X inactivation is a bit inefficient in some cells, but this doesn’t seem to be the case. X inactivation is established very early in development and is the most stable of all epigenetic processes. An alternative explanation was required.
The answer has its origin about 150 million years ago, when the XY system of sex determination in placental mammals first developed. The X and Y chromosomes are probably descendants of autosomes. The Y chromosome has changed dramatically, the X chromosome much less so[120]. However, both retain shadows of their autosomal past. There are regions on both the X and the Y called pseudoautosomal regions. The genes in these regions are found on both the X and the Y chromosome, just in the same way as pairs of autosomes have the same genes in the same positions, one inherited from each parent.
When an X chromosome inactivates, these pseudoautosomal regions are spared. This means that, unlike most X-linked genes, those in the pseudoautosomal regions don’t get switched off. Consequently, normal cells potentially express two copies of these genes in all cells. The two copies are expressed either from the two X chromosomes in a normal female or from the X and the Y in a normal male.
But in Turner’s syndrome, the affected female only has one X chromosome, so she expresses only one copy of the genes in the pseudoautosomal region, half as much as normal. In Trisomy X, on the other hand, there are three copies of the genes in the pseudoautosomal regions. As a result, the cells in an affected region will produce proteins from these genes at 50 per cent above the normal level.
120
For a good review of this, see Graves (2010),