Human Molecular Genetics by
Example of Insertion Mutation: Trinucleotides repeats (no frameshift)
In the previous lecture we discussed insetion mutation with multiple trinucleotide repeats which lead to
abnormal protein product. Here we will discuss Huntingtin disease: an example of trinucleotide insertion in
Huntington gene (HTT).
Huntingtin Disease (no frame shift)
Huntington disease (HD) is one of the trinucleotide repeat expansion disorders where the CAG repeat encodes
a polyglutamine tract within the coding region of the huntingtin gene (HTT) on chromosome
4p16.3(chromosome 4, short arm p and position on chromosome is 16.3).
The HTT gene carry the information for 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 and is essential for normal
development before birth.
Huntingtin is found in many of the body's tissues, with the highest levels of activity in the brain. Within
cells, this protein may be involved in chemical signaling, transporting materials, attaching (binding) to
proteins and other structures, and protecting the cell from self-destruction (apoptosis).
One region of the HTT gene contains a particular 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.
If the multiple repeats are inserted in the sequence then it will cause the disease known as Huntington
diseases.
Inheritance follows an autosomal dominant pattern, caused by a gain-of-function associated with the
repeat expansion.
Mild condition (no sign and symptoms appears) seen in carriers of 36–39 repeats, while the disease is
fully penetrant when 40 or more repeats are present. Alleles containing 250 and more repeats have been
reported.
The expanded 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. This process particularly affects regions
of the brain that help coordinate movement and control thinking and emotions (the striatum
and cerebral cortex).
The dysfunction and eventual death of neurons in these areas of the brain underlie the signs
and symptoms of Huntington disease.