Three types of Usher Syndrome, over a thousand varieties
At this moment, Usher Syndrome, also called the Syndrome of Usher, includes 10 different genes each of which are involved in the production of an Usher protein. The various genes are divided into three clinical images and indicated by a letter.
The division into the three clinical images is as follows:
Usher Syndrome type 1: children are born deaf and their organ of balance does not work. During childhood, the first signs of night-blindness and an ever narrowing field of vision appear.
Usher Syndrome type 2: children are born hard of hearing and the first signs of deteriorating eyesight appear around puberty.
Usher Syndrome type 3: children are born with good hearing or hard of hearing, but their hearing and eyesight deteriorate during childhood.
How do you live your life if you know that one day your world will be quiet and dark?
Watch the unique documentary ‘The small world of Machteld Cossee’ that has been provided with English subtitling.
Ten Usher genes
By now, more than 10 genes are known to be responsible for a certain type of Usher Syndrome. For each Usher gene a lot of different mutations are known. Mutations are changes in the hereditary material. Over 500 different mutations have been found in only the USH2A gene, all of which result in an improper (or insufficient) production of the Usherin protein. If there are no mutations (or 1 mutation) in the Usher gene, you do produce the Usher protein and your ears and eyes will function properly.
The Leiden Open Variation Database contains over 20K varieties of mutations in the 10 different USH genes. New screening technologies still result in new gene-related discoveries and these are added to the database in Leiden, the Netherlands.
For USH1E, 1H and 1K genomic regions have been defined, but genes with causal mutations have never been found in these regions. Expectations are that additional genetic analysis will show that these people have mutations in one of the known USH1 genes, as some technologies of the past appeared to be insufficient to discover all types of mutations.
In the past, researchers extensively studied how the various USH proteins bond together to form functional networks in the hair cells and photoreceptors. People think they completely know these networks for USH1, USH2 and USH3 and with that all associated proteins as well. These networks contain only one protein which at this moment is not an USH protein. This is PDZD7, which forms a part of the networks of USH2 proteins. Mutations in this protein seem to cause only deafness. Whirlin is suspected to be able to compensate the functioning of PDZD7 in the eye but not in the ear. The fact is that these two proteins are very much alike.
Based on the similarity of the development of the disease, it is assumed at this moment that four genes are possibly associated with USH, being PDZD7, HARS/USH3B, CEP250 and C2orf71.
The interpretation may sometimes vary in different laboratories, e.g. some literature accepts USH3B as USH gene and some literature only speaks of a possible association. In the Netherlands, people preferably take the work of Dr José Millán from Valencia, Spain, as a basis. He is the authority in the area of USH genetics in Europe. Look here for a complete list of the USH genes and mutations that are presently known. This list comes from the publicly accessible on-line platform OMIM (Mendelian Inheritance in Man).
Also, Usher genes are known in which mutations may lead to non-syndromic loss of hearing. In this case, no retinitis pigmentosa (RP) will be developed. These mutations are particularly found in Usher 1 genes and in the USH2D gene. Besides, the USH2A gene also knows mutations that cause non-syndromic retinitis pigmentosa. These patients suffer no or hardly any loss of hearing.
There still is a great variety in the seriousness of the disease, as this depends on the nature of the individual mutations and the specific combination of the USH mutations with patients.
Consequently, it is very well possible to suffer from Usher Syndrome type I but to have the loss of hearing and/or a stage of RP that is like someone suffering from type 2. Or you resemble a patient with Usher 3, but you have been diagnosed for Usher type 1.
2 mutations of the same Usher gene
People are diagnosed for Usher Syndrome, because they have two mutations in an Usher gene (the hereditary material). One mutation of the father and one of the mother. You will notdevelop Usher Syndrome if you, for example, inherit a mutation from the USH1 gene of your father and a mutation from the USH2 gene from your mother. Usher Syndrome only reveals itself if you inherit two mutations of the same Usher gene from both your father and your mother. The two mutations found in one of the Usher genes that are passed on from father and mother can be different (heterozygous) or identical (homozygous).
It is to be determined by means of an extensive examination whether (serious) loss of hearing and retinitis pigmentosa (retina degeneration – RP) are involved. In order to make the correct diagnosis, a DNA test is required. After all, more syndromes are known (although very rare) that also affect these two senses.
For a DNA test a small vial of blood is taken and a special laboratory will examine this for changes that can explain the loss of hearing and eyesight. Sometimes a vial of blood from one of the parents is also required to see if the changes are coming from one parent or have been inherited from both parents.
Watch this filmto see how a DNA test is done.
An early diagnosis is crucial for interventions with respect to loss of hearing, family planning as well as future therapies (or clinical trials). A correct diagnosis is also needed for the peace of mind to exclude a syndrome as well as to know whether someone qualifies for participation in clinical trials.
Early intervention with hearing aids and/or cochlear implants is required to enhance communication, education and social skills.
‘Next Generation Sequencing Technology’ is research focused on the molecular diagnosis of Usher Syndrome for not yet localised Usher mutations in both exons and introns with types 1, 2 and 3. Exons and introns are small parts of a gene that eventually contains the information for producing the correct protein. Read more about the ‘Genetic research exome sequencing’
The enormous variety in Usher genes, the sizes of these genes and the different mutations make the unravelling of Usher Syndrome really complex. Research into Usher Syndrome includes many challenges. See ‘The big challenges in research’
Do you suspect that you are suffering from Usher Syndrome but has this not yet been confirmed by a DNA test? Talk about this with your general practitioner and ask for a DNA test. Or contact the national Usher Syndrome expertise centre in Radboudumc by e-mail firstname.lastname@example.org
In the coming period, we will weekly give an update of the research into Usher Syndrome. We will first discuss all developments for Usher Syndrome 1 to be followed by Usher Syndrome 2 and 3. Finally, we will finish this series with an update on the developments in the area of retinal dystrophy, such as retinitis pigmentosa, and the developments in connection with severe deafness.
Some investigations will be conducted outside Europe and are in the animal models phase. Other investigations are in the trial phase (with test persons) or are about to start. The scientific developments go fast. As long as there is no affordable and effective treatment for Usher Syndrome, scientists will keep looking for a solution.
From DNA to protein
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)