HD (gene)

The HD (Huntington disease) gene, also called the IT15 ("interesting transcript 15") gene is a gene that codes for a 348 kDa protein called huntingtin. The exact function of this protein is not known, but it appears to play an important role in nerve cells. Within cells, huntingtin may be involved in signaling, transporting materials, binding proteins and other structures, and protecting against programmed cell death (apoptosis). The huntingtin protein is required for normal development before birth. It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.

The 5' end of the HD gene has a sequence of 3 DNA bases, cytosine-adenine-guanosine (CAG), coding for the amino acid glutamine, that is repeated multiple times. This region is called a trinucleotide repeat. Normal persons have a CAG repeat count of between 7 and 34 repeats.

The HD gene is located on the short (p) arm of chromosome 4 at position 16.3, from base pair 3,113,411 to base pair 3,282,655.

The HD gene and disease
Huntington's disease is caused by mutations in the HD gene, where the CAG repeat is expanded and unstable (an expanded trinucleotide repeat), repeating for 36 to more than 120 times. The CAG repeat expansion leads to the production of a huntingtin protein that contains an abnormal number of glutamines at the N-terminal. This makes it part of a class of neurodegenerative disorders known as CAG trinucleotide repeat disorders or polyglutamine disorders.

Enzymes in the cell often cut this elongated protein into fragments that have "sticky" ends. The protein fragments form abnormal clumps inside nerve cells and may attract other, normal proteins into the clumps. These nerve cells do not function properly and ultimately die. This process is particularly likely to occur in the striatum (a part of the brain that coordinates movement) and the frontal cortex (a part of the brain that controls thinking and emotions).

People with 36 to 40 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with more than 40 repeats will develop the disorder during a normal lifetime. When there are more than 100 CAG repeats, the person develops a severe form of HD known as Juvenile HD.

As the altered HD gene is passed from one generation to the next, the size of the CAG repeat expansion can change; it often increases in size, especially when it is inherited from the father. People with 27 to 35 CAG repeats have not been reported to develop Huntington disease, but their children are at risk of having the disease if the repeat expansion increases.