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Usher syndrome A report on the genetic disorder, its causes, and devastating effects. By Kathryn J Foley Biology 5293 1 The five sense organs that people use to explore and navigate their environment are: sight, hearing, touch, smell, and taste. For the majority of people these five senses function at a level that allows the individual to live a normal life which includes mainstream education and self-sufficiency as an adult. For a minority of people, however, this is not the case. Although the exact number is difficult to calculate, the U.S. Bureau of the Census reported that in 2009 there were 70,700 children ages 6 to 21 that had hearing impairments, 25,800 with visual impairments, and 1,400 that were deaf-blind. (U.S. Census 2012) For these individuals, especially the deafblind, common everyday task can become difficult and self-sufficiency is nearly impossible (Moller K et el. 2009). There are many different causes for these disabilities, including injury, infection, and genetic disorders. One of the genetic disorders is Usher syndrome. Usher syndrome (USH), which is an autosomal recessive genetic disorder that affects sight, hearing and balance, does not have a cure and can have devastating results if not diagnosed at a young age. This disorder is responsible for 50% of the deaf-blind population, as well as 3-6% of individuals that are congenitally deaf, and from 8-33% of people with retinitis pigmentosa (RP), a progressive retinal degeneration disease ( Yan D 2010). The characteristics of Usher syndrome (USH) was first described in 1858 by Albrecht von Graefe, a forerunner of the modern day ophthalmologist. He studied a family that had three brothers that were deaf and had retinitis pigmentosa. (K12 academics n.d.) Years later a British ophthalmologist, Charles Usher, established that the disorder was inherited, meaning that it is passed on from parent to child (Millan J et el. 2011). He arrived at this conclusion after studying 69 cases of people that were deaf/blind and their families (K12 academics n.d.) Usher syndrome is a recessive genetic disorder, which means that both parents must be carriers of the gene in order for their offspring to inherit the disorder. This explains why the majority of children with USH are born to parents with normal sight and hearing. Each parent will carry a recessive gene on one of their chromosomes, yet will not have any of the symptoms. With each birth, two individuals that are carriers of the Usher gene will have a 25% chance of having a child with Usher syndrome, a 50% chance of having a child that is a carrier of the usher gene, and a 25% chance of having a child that neither has Usher, nor is a carrier of the gene. (Campbell N 2008) The individuals that are carriers of the Usher gene will not show any symptoms of the disease. When a person who is a carrier reproduces with a person that does not have the Usher gene then each child has a 50% chance of being a carrier and 50% chance of not having the gene. The numbers of people world-wide that are affected by USH range, depending on population, from 3.5 to 6.2 per 100,000 persons born and in some populations, such as Israel, Finland, and the Accadians of Louisiana, there have been carrier rates as high as 1 in 100. ( Yan D 2010) The genes that are responsible for USH are carried on the autosomal chromosomes, which mean that it is not a sex-linked disorder; therefore both males and females can be affected. Although research is still being done, to date there have been nine different genes found that can cause USH (Bonnet C et el. 2011) These genes are important for the normal development and function of the ear and eye. The symptoms of Usher syndrome are hearing loss, lack of balance, and loss of hearing in the form of retinitis pigmentosa (RP), “a subset of hereditary retinal degenerations which affects more than one million people worldwide” (Pelino C 2009). For most people with RP the first signs are night-blindness, which usually occurs during teen-age years. This is followed by loss of peripheral vision which in time will narrow down to “tunnel vision”, the ability to only see straight ahead, and for some individual’s complete blindness (Pelino C 2009). The vision loss is caused by the degeneration of the photoreceptors, rods and cones, which are light sensitive receptors located at the back of the eye. For most people the rods are affected first, followed by loss of functioning cones (Genetics Home Reference 2007). The other symptoms of USH are hearing loss and vestibular dysfunction, a lack balance. To better understand the hearing loss associated with USH, it is important to have a basic understanding of how the ear works. According to Campbell, the ear consists of three parts, the outer ear, middle ear, and the inner ear. Sound waves are collected by the pinna, which is the external part of the ear that is visible, and channeled up the auditory canal to the tympanic membrane. This membrane separates the outer ear from the middle ear. The sound waves cause the tympanic membrane to vibrate, which in turn cause the three small bones of the middle ear to vibrate. These bones, the malleus, incus, and stapes transmit the vibrations to the oval window which is located beneath the stapes. The vibration of the oval window moves the fluid which is found in the part of the inner ear called the cochlea. It is within this “snail” shaped structure that the mechanism of hearing takes place (Campbell N 2008). The inside of the cochlea has two large canals which are called the upper vestibule canal and the lower tympanic canal. Separating these two canals is the cochlear duct. Both of the canals and the cochlear duct contain fluid. On the floor of the cochlear duct, the basilar membrane, is the organ of corti which contains hair cells that are the mechanoreceptors of the ear. When the fluid is moved in the vestibular canal by the vibration of the oval window it causes the basal membrane to vibrate which in turn causes microscopic hair cells to bend. These hair cells send signals to the sensory neurons which carries the information to the brain. Each hair cell has a bundle of rod shaped hairs projecting from it. Each of these hairs has a core of actin filaments. (Campbell N 2008). Studies have shown that the proteins made by the usher genes are important for the normal development and cohesion of these hair bundles in the inner ear ( Yan D 2010). “The USH proteins mainly colocalize in the stereocilia and at the synaptic regions of the hair cells of the inner ear. Stereocilia are mechanosensing organelles located at the apical surface of both the auditory and vestibular hair cells. The bending of the hair bundle by a sound wave opens mechanically the gated transduction channels at the tip of the stereocilla, initiating the electrical signal cascade for sound perception.” ( Yan D 2010). If the hair bundles are misshaped, then they will not be able to function correctly and hearing loss will occur. Within the inner ear are also the structures that are responsible for balance, the three semicircular canals and the utricle and saccule. The three semicircular canals are each located at a different angle and this detects the movement of the head turning. The utricle and saccule are responsible for telling the body which way is up and also acceleration. The mechanism for this is much like hearing. There are hair cells located at the base of the canals which respond to the fluid when it moves and then sends signals to the nerves which carry it to the brain (Campbell N 2008) As in the organ of corti, when the structure of the hair cells are flawed, they can not function correctly, thus the signals are not sent to the brain as they should be. Based on the age of onset of these three characteristics, loss of vision, hearing and balance, and the genes that are involved, Usher syndrome has been divided into three groups, USH1, USH2, and USH3. USH 1 is the most severe form of the disease and accounts for 30-40% of all Usher syndrome cases (Millan J et el. 2011). Persons born with USH1 will have profound hearing loss from birth, as well as vestibular dysfunction. Persons usually will not begin to walk until age two and many will never develop speech (Millan J et el. 2011). This form of Ushers is the most frequent cause of deaf-blindness in humans (Yan D et el. 2011). Individuals with this form of Usher syndrome will also begin to lose their eye sight usually before they reach puberty (Yan D 2010). For these reasons, early diagnosis is critical so that patients can get physical therapy and cochlear implants; otherwise the ability to communicate can be lost (Bonnet C et el. 2011). For USH 1 there have been seven genetic locations mapped on different chromosomes, with five of the genes having been cloned. These genes are: “the actin-based motor protein myosin VIIa (Myo7a, USH1B), two cadherin-related proteins, otocadherin or cadherin 23(Cdh23, USH1D) and protocadherin 15 (Pcdh 15, USH1F), and two scaffold proteins, harmonin (USH1C) and sans (USH1G)”. These proteins are found in the hair cells of the inner ear where they are present in varying degrees at different times durning development ( Yan D 2010). Studies done by Yan D et el. 2011, have shown that in mice mutations have been found for all of the known USH 1 genes and studies have been conducted to see how the scaffold protein harmonin (USH1C) affects the formation of the hair bundles in the inner ear. These studies have shown that from birth to day 120, mice that were homozygous mutant (USH1c-/-) “ showed progressively disorganized outer hair cell (OHC) stereocilia compared with the wellorganized pattern and rigid structure typical of normal stereocilia.” Normal stereocilia have a ‘V’ shaped bundle whereas the mutant mice displayed a more disorganized arrangement. ( Yan D et el. 2011) Studies such as these have helped scientist understand the morphology of the inner ear and how it works. The second form of Usher syndrome, USH2, is also the most common and is characterized by patients having intact vestibular responses, retinitis pigmentosa and hearing loss of the higher frequency sounds that comes on slowly with age (Leijendeckers JM 2009). Individuals with USH2 are able to develop normal speech and loss of eye sight usually does not begin until age 15 ( Yan D 2010). As of this writing, three genetic locations have been found that are believed to be responsible for USH2. These locations are USH2A, USH2C, and USH2D. Of these three genes USH2a, which encodes for the protein usherin, has been shown to be involved in 55%-90% of USH2 cases (Bonnet C et el. 2011). The USH2a gene is very large and mutational screening has been done which shows that a mutation, c.2299delG accounts for up to 45% of all the mutated alleles. Studies have also shown that the mutation c.2299delG “appears to be an ancestral mutation of European origin which spread from Europe to other regions of the world during colonization.” (Millan J 2011). As in USH1, these genes encode for proteins that are present in the hair cells of the inner ear. Usherin is believed to be important for the formation of ankle-links, which are filamentous lateral links that connect stereocilia at the base (Adato A et el. 2005). The third form of Usher syndrome USH3 is the rarest form worldwide, accounting for only 1-6% of all Usher cases, with the exception of the Ashkenazi Jews and in the Finnish population where this form makes up to 40% of all cases. (Vastinsalo H 2011) “USH3 is characterized by progressive hearing loss, retinitis pigmetosa, and variable vestibular dysfunction.” (Vastinsalo H 2011). With this form the symptoms of RP usually start to appear by the age of twenty. Hearing loss is similar to USH2, with onset beginning in the first to third decade of life, which allows the individual to develop good speech patterns before total loss of hearing occurs. In 50% of USH3 cases vestibular dysfunction is present (Millan J et el. 2011) USH3A, which encodes for clarin-1, is the only known genetic location for Usher syndrome 3 (Yan D 2010). Clarin-1encodes for a protein that belongs to a large family of transmembrane proteins that takes part in a number of functions which include; “regulating cell morphology, motility, invasion, and signaling”(Geng R 2009). Although the exact function of Clrn-1 in the inner ear is not known, studies using mice as models have suggested that it may play a part in hair cell development and function. “Expression was most apparent in the spiral ganglion cells (SGCs) and in the hair cells of the basal turn of the cochlea compared with the apical turns at early stages.” (Geng R 2009). The study conducted by Geng (2009) also showed that expression of Clrn-1 was present in the inner ear during all stages of development, from 16.5 days before birth to 5 days after birth. Many of the genes that are responsible for Usher syndrome have now been mapped, yet it is apparent that the exact way in which they work together has not yet been fully explained. Various studies have found that USH1 and USH2 proteins work together to make up a “protein network known as Usher interactome”. “The central core of the interactome is formed by the PDZ domain containing the homologues harmonin and whirlin and the microtubule-associated protein SANS, with the remaining USH proteins attached to this core.” USH 1 and USH2 genes also interact in the eye, specifically in the ciliary/periciliary region of cone and rod photoreceptors (Millan J et el. 2011) Table 1. The three subtypes of Usher syndrome and their symptoms Type 1 Profound deafness in both ears from birth Type 2 Moderate to severe hearing loss from birth Vision Decreased night vision before age 10 Vestibular function (balance) Balance problems from birth Decreased night vision begins in late childhood or teens Normal Hearing Type 3 Normal at birth; progressive loss in childhood or early teens Varies in severity Normal to nearnormal, chance of later problems Until now, the main body of the paper has focused on the biological aspects of Usher syndrome, but what about the social ramifications of this disease. Early detection, especially in the case of patients with USH1, is critical so that proper help can be given to the individual, yet often the disease is misdiagnosed. Other disorders such as Bardet-Biedl syndrome and MohrTranebjaerg syndrome can show the same clinical symptoms as USH, as well as rubella although that is not as common today as it was in the 1970s and before (Millan J et el. 2011). Often parents do not know to test for USH because there is no family history of it. At times it is not until vision problems begin to occur that the correct diagnosis is made. Today there are genetic test available for locate a few of the genes that are connected to USH, but much of the diagnostic procedures are still based on clinical evaluations (Health n.d.) When diagnosed in time, patients can use cochlear implants to help them hear and develop speech, if not then as the ability to see and hear diminish, so will the ability to communicate to others (Pelino c 2009) There are symptoms that a parent should watch for if they have a child that is born with profound hearing loss. Because night-blindness is the first sign of RP, parents should observe their infant and see if they can find their bottle in a darkened room (Davenport n.d.) Other signs that are present as the child gets older are how well they can see outside at night. Do they always need to hold onto a rail or an adult’s hand? The other symptom that should be a strong indicator that a deaf child has USH is their balance and coordination. Many children with USH I will have difficulty learning to crawl. They may prefer to roll or even have a “five-point” crawl in which they keep their head on the ground (Health n.d.). Walking will also be delayed, often until 18-24 months. Once the child learns how to walk and maneuver they have no problem running and playing. Games that involve twirling are especially fun because these children do not get dizzy (Health n.d.) Today there is no cure for Usher syndrome. Cochlear implants have been used sucsesfully in all three types of USH to aid in hearing loss. This allows the child to learn oral language and for USH II patients they are often able to function well in mainstream schools (Health n.d.). Although there is no treatment that will stop the progression of retinitis pigmentosa there are optical devices available such as reverse telescopes, amophic lenses, and mirrors that are useful in enhancing a patient’s functional visual field. To help with night vision a wide-angle mobility lamp or “night-scope” can also be employed (Pelino c 2009). Other studies have centered on vitamin A palmitate supplements and have found that a high daily intake, (15,000 IU/Day) can slow down the progress of retinitis pigmentosa. There is however risk involved with this high of a dose, one of them being a risk of birth defects, so women who are pregnant cannot use this therapy (Pelino c 2009). As an individual with Usher syndrome loses their sight, there are various ways in which they can still communicate with the people around them. Tactile sign language is a form of signing in which the deaf-blind individual places his/her hands over the other person’s hands so that they can follow the movements (Deaf-Blind n.d.). Another way to communicate with nonsigning people is to use the screen Braille communicator (SBC). This is a small hand held device that has a QWERTY keyboard on one side and a braille display on the other side. The sighted person can type into the machine and it will be displayed in braille (Deaf-Blind n.d.). Modern technology is making it easier to be able to communicate and to function. Usher syndrome is a rare disease and therefore not as recognized, or well-funded as other genetic diseases. But, because of the terrible trauma and isolation that it causes it is important to continue to conduct, and fund, research that will help to better understand the genes involved. As more information is learned perhaps a cure could be found using gene therapy. Even if the best that can be hoped for is more accurate diagnoses procedures, this would help the patients receive as much help as possible so that they could better prepare themselves for the future. Bibliography Aller E, Larrieu L, Jaijo T, Baux D, Espinos C, Gonzalez-Candelas F, Najera C, Palau F, Claustres M, Roux A, Millan J. 2010.The USH2Ac.2299 del G mutation: dating its common orgin in a Southern European population. EJHG(18): 788-793. Bonnet C, M'hamed G, Marlin S, Levilliers J, Hardelin J, Parodi M, Niasme-Grare M, Zelenika D, Delepine M, Feldmann D, Jonard L, El-Amraoui A, Weil D, Delobel B, Vincent C, Dollfus H, Eliot M, David A, Calais C, Vigneron J, Montaut-Verient B, Bonneau D,. 2011.Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis. Orphanet Journal of Rare Diseases 6:21: 21-40. Campbell N, Reece J, Cain M, Wasserman S, Minorsky P, Jackson R.2008.Biology 8th edition. 276-280. San Francisco: Pearson education Genetics Home Reference.2007.Usher syndrome. U.S. National Library of Medicine. http://ghr.nlm.nih.gov/condition/usher-syndrome/show/print (accessed March 4, 2012). Geng R, geller S, Hayashi T, Ray C, Reh T, Bermingham-McDonogh O, Jones S, Wright C, Melki S, Imanishi Y, Palezewski K, Alagramam K, Flannery J.2009.Usher syndrome IIIA gene clarin-1 is essential for hair cell function and associated neural activation." hum Mol Genet. 18(15):2748-2760. Leijendeckers JM, Pennings RJE, Snik AFM, Bosman AJ, Cremers CWRJ. 2009. Audiometric characteristics of USH2a patients. Audiol Neurootol. 14(4):223-31. Millan J, Aller E, Jaijo T, Blanco-Kelly F, Gimenez-Pardo A, Ayuso C. 2011.An update on the genetics of Usher syndrome (Review). Journal of Ophthalmology ID 417217: 1-8. Pelino c, Pizzimenti J. 2009.Retinitis Pigmentosa-Strategies for the Present and Future. AOE, 2009: 2830. Vastinsalo H, Jalkanen R, Dinculescu A, Isosomppi J, Geller S, Flannery J, Hauswirth W, Sankila E. 2011.Alterative splice variants of the USH3A gene Clarin 1 (CLRN1). EJHM: 19:30-35. Yan D, Kamiya K, Ouyang X, Liu X. 2011.Analysis of subcellular localization of Myo7a, Pcdh15 and sans in USH1c knockout mice. Int J Exp Pathol. 92(1):66-71. Yan D, Liu X. 2010.Genetics and pathological mechanisms of Usher syndrome (Review). Journal of Human genetics. 55:327-335.