This week in science history saw, in 1993, the discovery by a team in America of the single gene involved in Huntington’s disease; a neurodegenerative disorder that causes characteristic jerky movements, loss of memory and muscle control. It is rare, affecting only 7 in 100,000 people – compared to 1 in 3 for cancer, but it is more common than some other genetic diseases, such as achondroplasia (or dwarfism) that affects only 4 in 100,000.
Huntington’s was one of the first genetic diseases to have its gene sequence mapped – following the sequencing of the gene for cystic fibrosis in 1989.
Gene sequencing began in the 1970s, working on viruses, particularly ones called bacteriophages – viruses that attack bacteria. By 1991, when the Human Genome Project began – it’s aim to sequence the entire human genome – sequencing was accurate but still relatively slow.
But first, a short introduction to the genetics of Huntington’s. Humans have all their DNA arranged in 23 pairs of chromosomes – one pair of which is the sex chromosomes, the X and Y that determine what gender you are.
The group that worked on the Huntington’s gene found that it was located on chromosome 4. The gene itself codes for a protein called Huntingtin, which is essential for brain development and helps to produce a chemical that encourages nerve cell growth.
Proteins are made up of amino acids, and DNA contains the information on which amino acids to put into which order for every protein in our bodies. This order is determined by combinations of the *bases* adenine, thymine, cytosine and guanine, or A, T, C and G. Each amino acid is coded for by three of these bases – for example GGA codes for glycine.
At one end of the huntingtin gene, there are several repeats of the bases CAG, which leads to a chain of glutamines on the end of the Huntingtin protein. In people with the normal copy of the gene, there can be up to 36 of these CAG repeats, but in those with the mutant form, there can be as many as 70 or more.
When there are this many glutamines on the end of the protein, it changes shape and can no longer perform its job properly – meaning that the nerve cells in the brain that rely on it to make and maintain new connections can degenerate and die, especially in the areas controlling movement – causing the movements that give the disease its other name of Huntington’s Chorea, and loss of coordination then eventually loss of muscular control throughout the body.
The group also found that the number of repeats determined when in life the disease would start – between 36-45 repeats and you might never realise you had it as it would start so late in life you would probably die of something else first. With over 45, the disease usually manifests in your 40s, and with over 70, juvenile HD develops, with all the symptoms appearing in teens or 20s, and progressing rapidly, leading to early death.
Since this paper was published, genetic sequencing has come on in leaps and bounds, with the Human Genome Project completed ahead of schedule in 2001. Many other genetic disorders have been sequences. This allows for testing methods to be developed – for adults and for pregnant women who may want to terminate a pregnancy if the child would have a genetic disease. In the developing fields of gene therapy and RNAi it also allows affected genes to be pinpointed and targeted for therapy and treatment. In the future, it may be that we can treat all genetic diseases, with these early discoveries providing the beginnings of an important series of breakthroughs…
The paper is available here: <cite>Macdonald, M (March 1993). "A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group". Cell 72 (6): 971–83. doi:10.1016/0092-8674(93)90585-E.</cite>