Ushers

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The most common type of deaf-blindness disease in the world is Usher Syndrome. Usher Syndrome is a clinically and genetically heterogeneous disease. It is inherited in an autosomal recessive inheritance pattern. Worldwide, the chance of a baby being born with Ushers Syndrome is approximately 1 in every 25,000 babies. To date, there are roughly 50,000 people with Ushers Syndrome living in the United States. As stated above, Ushers Syndrome is an inherited disease characterized by hearing impairment and progressive vision loss. The vision loss is due to retinitis pigmentosa, which is a degenerative condition of the retina and this usually appears during adolescence or early adulthood. The balance of an individual is usually also affected with retinitis pigmentosa. The other part of Usher Syndrome, the hearing loss, is due to a genetic mutation affecting nerve cells in the cochlea, a sound transmitting structure in the inner ear. The same genetic effect also adversely affects photoreceptor cells in the retina leading to vision loss.

Usher Syndrome is a heterogeneous disease meaning it comes in several different types, in our case 3 and they are called Usher Syndrome 1, Usher Syndrome 2, and Usher Syndrome 3. They are numbered in decreasing range of severity. USH1 patients are deaf at birth and onset of retinitis pigmentosa is prepubertal and most of them have vestibular dysfunction. USH2, on the other hand is characterized by a moderate to severe hearing loss at birth and to retinitis pigmentosa can be diagnosed at puberty. USH3 is further down the chain meaning these same symptoms apply but they actually show up later on in life. Usher Syndrome can also be associated with reduced odor identification, impaired sperm mobility and mental deficiency.

Of the eleven loci responsible for this syndrome, nine have already been identified. The proteins that are encoded by these genes are actually part of a dynamic protein complex that occurs in the hair cells of the inner ear and in the photoreceptors of the retina. The Usher protein complex is required in the morphogenesis of the stereocilia boundle in hair cells and in the calycal processes of photoreceptor cells. Other proteins are always interacting with this complex and this makes us visualize how important this complex is in regards to the cells biology. The Usher protein complex can also be linked to the cadherins/catenins in protein complexes providing a main role in tissue organization and cell to cell interactions along with integrin transmembrane signaling network. The main causative genes for Usher syndrome encode a set of proteins named USH1 proteins: myosin VIIa, cadherin 23, protocadherin 15, harmonin and sans. These proteins are components of different stereocilia links and together form supramolecular complexes. These proteins are present in the hair bundle during its early development. Another thing is that they are key components of the mechanoelectrical transduction machinery. Sometimes, the phenotype of USH1 patients caused by mutations in different USH1 genes cannot be distinguished, meaning that the USH1 proteins may be implicated in the same cellular functions. The early cochlear hair bundle anomalies associated with USH1 gene defects alone account for the congenital deafness of USH1 patients. The USH2A and USH2C genes code for the transmembrane protein which are usherin and Vlgr1 (a very large G protein-coupled receptor-1). The USH2D gene encodes whirlin which is a PDZ domain-containing protein and that is the closest homolog of harmonin. These three proteins are colocated at the stereocilia base during development, up to almost the final maturation of the hair bundle. Myosin VIIa generates force by using actin filaments as a substrate and also makes movements in response to the hydrolysis of ATP. It is all around the hair cell and may be concentrated in some particular regions of the hair bundle. Cadherin-23 and protocadherin-15 are transmembrane...
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