Chromosome X

Some diseases affect males but not females in a family. Such diseases, called X-linked recessives, are often caused by mutations in genes located on the X chromosome, called X-linked genes. An X-linked disease is transmitted from the mother, not from the father, to an affected male, and an affected male will transmit a copy of the mutant gene to all his daughters. A famous example of an X-linked disease is hemophilia A. The blood of hemophiliac males fails to coagulate properly, leading to thinning of the blood and unstoppable bleeding after injury. This disease was recognized in the royal family of Queen Victoria, where examination of the huge pedigree readily confirmed recessive X-linked inheritance. Only males were affected, having inherited an X chromosome with a copy of a mutated gene from their healthy mothers, who were carriers of the disease. The mutated gene in hemophilia A was identified as factor VIII, a gene that encodes a protein essential for proper clotting of the blood. Males with a mutated gene cannot compensate since they have only one X chromosome, whereas female carriers have one normal gene that can compensate for the diseased gene. This typical recessive X-linked inheritance has been described for a variety of genes.

Figure 2. Karyotype of a normal human male. Each of the first twenty-two chromosomes has two copies. The last set is the sex chromosomes, and consists of one X and one Y chromosome.

Dominant X-linked mutations, in which female carriers with just one mutated copy of the gene are affected, are rare. One example of such a disease is vitamin D-resistant rickets, in which people develop skeletal deformities. Generally, the disease is less severe in females than in males, because of X inactivation (see below). A famous X-linked disorder with inheritance that cannot be classified as either recessive or dominant is fragile X mental retardation. The fragile X chromosome bears its name because it displays a site susceptible to chromosome breakage. The mutated gene at the site contains a triplet repeat expansion, in which a series of three consecutive bases are copied multiple times. This causes the gene to be turned off by secondary changes in its structure. Affected males have severe mental retardation and female carriers can also be affected.