We have two copies of each gene in our DNA, one from the mother and one from the father. People suffering from Usher Syndrome have mutations (harmful changes) in both copies of one Usher gene. A person can obtain two identical mutations from both parents. This is what we call homozygous changes. Two different mutations are called heterozygous changes. Here we discuss various types of mutations.
Over 1000 different mutations have been described for theUsher-genes. These mutations can largely be divided into differents types, being nonsense mutations, splicing mutations, deletions and insertions and missense mutations.
Usher Syndrome patients show all these different types of mutations. Irrespective of the type of mutation (nonsense, splicing or missense) or the Usher gene (USH1, USH2 or USH3) in which they are found, these all lead to loss of the functioning of Usher proteins in the eye and ear. The large number of mutations, of some of which it is not even known yet whether they actually cause Usher Syndrome, makes the genetics and the diagnosis of Usher Syndrome really complex.
The DNA is a long chain of building blocks, also called nucleotides (or bases). The nucleotides in the DNA are:
- Adenine (A),
- Cytosine (C),
- Guanine (G) and
- Thymine (T).
At first sight, the DNA seems to be a random sequence of As, Cs, Gs and Ts, but the order of these letters is highly important. In fact, the order of the letters defines the genetic code and determines whether a good protein is produced.
Every cell of our body contains a kind of “protein machine”. This machine reads the blueprint of the genes and uses this information to produce proteins. When this machine comes across a so-called “nonsense” mutation in a gene, the production of the protein that is coded by this specific gene stops. This results in a shortened, non-functional or even absent protein. About 35% of all mutations (changes) in the USH2A gene are “nonsense” mutations.
A deletion means that a small piece of genetic code has disappeared. This results in a shortened, non-functional or absent protein during the protein production.
An insertion means that an extra piece of genetic code has been inserted into a gene. This leads to a disruption of the protein production and, consequently, a non-functional or absent protein.
A nonsense, deletions and insertions mutations gives the above-mentioned ‘protein production machine’ the signal to stop reading the mRNA. As a result of this, no normal protein is produced any longer.
In case of a fault in the pre-mRNA splicing, a part of the gene is not included in the mRNA (exon skipping) or a wrong part is included in the mRNA (pseudo-exon).
A splicing mutations gives the above-mentioned ‘protein production machine’ the signal to stop reading the mRNA. As a result of this, no normal protein is produced any longer. A splicing mutation also lead to a stop signal and therefore we classify them with the nonsense mutations.
Proteins consist of a chain of amino acids. During the protein production process, a “missense” mutation in the genetic code changes an amino acid into another amino acid. In this case the protein is produced, but it looses its function because of this one fault.
The missense mutation is a change which causes wrong information being passed on to the ‘protein production machine’. As opposed to nonsense mutations and splicing mutations, the ‘protein producing machine’ will not stop, but creates a small deviation in the protein. Because of this small deviation, the protein is no longer functional.
Do you want to know what type of mutation you have and how to read the genetic report?