The exact sequence and location of the gene that causes Huntington’s disease was published in 1993, but the hunt had been on for some time. Today, anyone can search for the sequence of the huntingtin gene on the internet (in fact, here it is, if you want to scroll through a lot of A, G, C, and T), but the initial discovery was a painstaking and labor-intensive process. It’s a bit like using a map of the whole world to find one house – you’d have to use landmarks to get down to the close vicinity of the location. Perhaps first a continent, then a country, then a city, a neighborhood, a nearby park, a street name. Similarly, researchers used landmarks on chromosomes to get closer and closer to the huntingtin gene.
In August of 1987 HD researchers led by Dr. James Gusella reached a major milestone in their search, reporting that they had found huntingtin’s neighborhood, at the tip of the 4th chromosome. It was a big step towards identifying the gene. Dr. Gusella has continued to make major contributions to HD genetics research, including more recent findings about CAG repeats and age of onset, shared at an HDSA research webinar last November.
Another historical finding in early August has to do with inheritance of the HD gene. When HD is passed down from generation to generation, the length of the CAG repeat can sometimes increase a little (or a lot). This is important because the onset of symptoms is influenced by CAG repeat length. It’s very variable, and also depends on many other factors, but more CAG repeats can lead to an earlier onset. A person with 41 CAGs in their HD gene will sometimes pass down more CAG repeats to their child (like 42, 43, 50, or more). This phenomenon is called anticipation, and it’s part of the reason that people in the same family sometimes get symptoms at such different ages.
In August of 1995, researchers studied hundreds of families and published key findings about differences in the HD gene between parents and children. They found that when dads with HD passed the gene to their children, the CAG number was more likely to jump much higher between generations, sometimes leading to Juvenile Huntington’s Disease (JHD). Understanding this aspect of HD inheritance has helped to better guide the diagnosis of JHD. If you want a deeper look, the original published article can be read here.