The hereditary material of each person is stored in the DNA. The DNA consists of many genes. Each gene contains the code for the production of a protein. Proteins are the building blocks of our bodies. Reading this code for producing a protein is a complicated process.
Each gene has been built up from exons and introns. An exon (derived from Expressed region) is a coding part of a gene and contains the information for building a protein. An intron is the region between the exons. The introns do not contain information required for building a protein.
After the copying process, the introns are removed from the pre-mRNA in order to create the mRNA. The mRNA is a sort of building plan for producing a protein.
In this building plan all exons have been connected with each other. The separation of introns and exons is also called ‘splicing’.
The exons form a readable text and the ‘protein production machine’ can read this information and use it to produce a functional protein. Consequently, a well-functioning inner ear and retina require correctly produced Usher proteins.
Mutations in one Usher-gene
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.
A stop signal A nonsense mutation 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 nonsense mutation can have various causes:
- the mutation creates a stop signal directly at pre-mRNA level. The copying of the gene stops.
- The stop signal is the result of insertion or deletion in the mRNA. In case of an insertion something extra is added, which makes the mRNA unreadable and in case of a deletion information is removed from the mRNA. What happens next with the information for protein production can be compared with a written text in which the spaces are wrongly placed. In both cases the ‘protein building machine’ cannot properly read the information and this prematurely stops the process.
- the mutation causes a fault in the conversion from pre-mRNA to mRNA. During this process, the exons and introns are incorrectly separated. We also call this the splicing mutations.
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). Both options also lead to a stop signal and therefore we classify them with the nonsense mutations.
Causes wrong information
Finally, we also have the missense mutation. This 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.
The genetics of Usher Syndrome is really complex
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.
Usher Syndrome and DNA diagnostics
Research into unravelling and a treatment for Usher Syndrome costs a lot of money. As Usher Syndrome is a rare disease, the governments makes little money available to stimulate research. The mission of the Usher Syndrome Foundation is: ‘A treatment for Usher Syndrome in 2025!” Help us and donate for scientific research, giving all people suffering from Usher Syndrome a realistic prospect of treatment.
Also read ‘‘Who knows USHIE?’ and read how USHIE you can help to collect a million euros for scientific research
This series was established thanks to: Ivonne Bressers, Cindy Boer en Willem Quite (Ushersyndroom Foundation),
Ronald Pennings, Erwin van Wijk, Erik de Vrieze en Bas Hartel (Radboudumc),
Lisé Nijman (English translations)