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Mutations in the HTT gene cause Huntington disease. The HTT gene provides instructions for making a protein called huntingtin. Although the exact function of this protein is unknown, it appears to play an important role in nerve cells (neurons) in the brain. The HTT mutation that causes Huntington disease involves a DNA segment known as a CAG trinucleotide repeat. This segment is made up of a series of three DNA building blocks (cytosine, adenine, and guanine) that appear multiple times in a row. Normally, the CAG segment is repeated 10 to 35 times within the gene. In people with Huntington disease, the CAG segment is repeated 36 to more than 120 times. People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with 40 or more repeats almost always develop the disorder. An increase in the size of the CAG segment leads to the production of an abnormally long version of the huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington disease.

As the altered HTT gene is passed from one generation to the next, the size of the CAG trinucleotide repeat often increases in size. A larger number of repeats is usually associated with an earlier onset of signs and symptoms. This phenomenon is called anticipation. People with the adult-onset form of Huntington disease typically have 40 to 50 CAG repeats in the HTT gene, while people with the juvenile form of the disorder tend to have more than 60 CAG repeats.

Of the four described Huntington disease-like (HDL) syndromes, HDL4 appears to be the most common. HDL2 is the second most common and occurs almost exclusively in people of African heritage (especially black South Africans). HDL1 has been reported in only one family. HDL3 has been found in two families, both of which were from Saudi Arabia.

In about one percent of people with the characteristic features of Huntington disease no mutation in the HD gene has been identified. However, mutations in the PRNP, JPH3, and TBP genes have been found to cause the signs and symptoms in some of these individuals. HDL1 is caused by mutations in the PRNP gene, while HDL2 results from mutations in JPH3. Mutations in the TBP gene are responsible for HDL4
(also known as spinocerebellar ataxia type 17). The genetic cause of HDL3 is unknown.

One region of the JPH3 gene contains a CAG/CTG trinucleotide repeat.  Normally, the CAG/CTG segment is repeated 6 to 28 times within the gene.  People with HDL2 have 44 to 59 CAG/CTG repeats. People with 29 to about 43 CAG/CTG repeats may or may not develop the signs and symptoms of HDL2.

Normally, the CAG/CAA segment is repeated 25 to 42 times within the TBP gene. People with HDL4 have 43 to 66 CAG/CAA repeats. People with 43 to 48 CAG/CAA repeats may or may not have signs and symptoms, while people with 49 or more repeats almost always develop the disorder.

The PRNP mutations associated with HDL1 involve a segment of DNA called an octapeptide repeat. This segment provides instructions for making eight protein building blocks (amino acids) that are linked to form a protein fragment called a peptide. The octapeptide repeat is normally repeated five times in the PRNP gene. In people with HDL1, this segment is repeated eleven or thirteen times. An increase in the size
of the octapeptide repeat leads to the production of an abnormally long version of PrP. It is unclear how the abnormal protein damages and ultimately destroys neurons, leading to the characteristic features of HDL1.