The Epigenetics Revolution

Females have two copies of the ECTODYSPLASIN-A gene, one on each of their X chromosomes. In female carriers of X-linked hypohidrotic ectodermal dysplasia, one X carries a normal copy of the gene, and one a mutated version. There will be random inactivation of one X chromosome in different cells. This means some cells will express a normal copy of ECTODYSPLASIN-A. Other cells will randomly shut down the X carrying the normal copy of the gene, and won’t be able to express the ECTODYSPLASIN-A protein. Because of the clonal way in which areas of skin develop, just like in the tortoiseshell cat, these women have some patches of skin that express ECTODYSPLASIN-A and some that don’t. Where there’s no ECTODYSPLASIN-A, the skin can’t form sweat glands. As a consequence, these women have patches of skin that can sweat and cool down, and others that can’t.

Random X inactivation can significantly influence how females are affected by mutations in genes on the X chromosome. This depends not just on the type of gene that is mutated but also on the tissues that express and require the protein encoded by that gene. The disease called mucopolysaccharidosis II (MPSII) is caused by mutations in the LYSOSOMAL IDURONATE-2-SULFATASE gene, on the X chromosome. Boys with this mutation on their single X chromosome are unable to break down certain large molecules and these build up to toxic levels in cells. The main symptoms include airway infections, short stature and enlargement of the spleen and liver. Severely affected boys also suffer mental retardation, and may die in their teenage years.

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.