| Usher syndrome | |
|---|---|
| Other names | Usher–Hallgren syndrome |
 | |
| Usher syndrome is inherited in anautosomal recessive pattern. The genes implicated in Usher syndrome are described below. | |
| Specialty | Ophthalmology  |
Usher syndrome, also known asHallgren syndrome,Usher–Hallgren syndrome,retinitis pigmentosa–dysacusis syndrome ordystrophia retinae dysacusis syndrome,[1] is a raregenetic disorder caused by a mutation in any one of at least 11genes resulting in a combination ofhearing loss andvisual impairment. It is the most common cause ofdeafblindness and is at present incurable.
Usher syndrome is classed into three subtypes (I, II, and III) according to the genes responsible and the onset of deafness. All three subtypes are caused by mutations in genes involved in the function of theinner ear andretina. These mutations are inherited in anautosomal recessive pattern.
The occurrence of Usher syndrome varies across the world and across the different syndrome types, with rates as high as 1 in 12,500 in Germany[2] to as low as 1 in 28,000 in Norway.[3] Type I is most common inAshkenazi Jewish andAcadian populations, and type III is rarely found outside Ashkenazi Jewish andFinnish[4] populations. Usher syndrome is named after Scottish ophthalmologistCharles Usher, who examined the pathology and transmission of the syndrome in 1914.
People with Usher I are born profoundly deaf and begin to lose theirvision in the first decade of life. They also exhibitbalance difficulties and learn to walk slowly as children, due to problems in theirvestibular system.[citation needed]
Usher syndrome type I can be caused by mutations in any one of several different genes:CDH23,MYO7A,PCDH15,USH1C andUSH1G. These genes function in the development and maintenance ofinner ear structures such as hair cells (stereocilia), which transmit sound and motion signals to the brain. Alterations in these genes can cause an inability to maintain balance (vestibular dysfunction) and hearing loss. The genes also play a role in the development and stability of the retina by influencing the structure and function of both the rod photoreceptor cells and supporting cells called theretinal pigmented epithelium. Mutations that affect the normal function of these genes can result inretinitis pigmentosa and resultant vision loss.[citation needed]
Worldwide, the estimated prevalence of Usher syndrome type I is 3 to 6 per 100,000 people in the general population. Type I is more common in people ofAshkenazi Jewish ancestry (central and eastern European) and in the French-Acadian populations (Louisiana).[5] Among Acadians, research into haplotype data is consistent with one single mutation being responsible for all cases of Usher syndrome type I.[5]
People with Usher II are not born deaf and are generallyhard-of-hearing rather than deaf, and their hearing does not degrade over time;[6] moreover, they do not seem to have noticeable problems with balance.[7] They also begin to lose their vision later (in the second decade of life) and may preserve some vision even into middle age.[citation needed]
Usher syndrome type II may be caused by mutations in any of three different genes:USH2A,GPR98 andDFNB31. The protein encoded by the USH2Agene, usherin, is located in the supportive tissue in the inner ear and retina. Usherin is critical for the proper development and maintenance of these structures, which may help explain its role in hearing and vision loss. The location and function of the other two proteins are not yet known.[citation needed]
Usher syndrome type II occurs at least as frequently as type I, but because type II may be underdiagnosed or more difficult to detect, it could be up to three times as common as type I.[citation needed]
People with Usher syndrome III are not born deaf but experience a progressive loss of hearing, and roughly half have balance difficulties.[citation needed]
Mutations in only one gene,CLRN1, have been linked to Usher syndrome type III.CLRN1 encodes clarin-1, a protein important for the development and maintenance of the inner ear and retina. However, the protein's function in these structures, and how its mutation causes hearing and vision loss, is still poorly understood.[citation needed]
The frequency of Usher syndrome type III is significant only in theFinnish population[4] as well as the population ofBirmingham, UK,[8] and individuals of Ashkenazi Jewish heritage. It has been noted rarely in a few other ethnic groups.[citation needed]
Usher syndrome is characterized byhearing loss and a gradualvisual impairment. The hearing loss is caused by a defectiveinner ear, whereas the vision loss results fromretinitis pigmentosa (RP), a degeneration of the retinal cells. Usually, therod cells of theretina are affected first, leading to early night blindness (nyctalopia) and the gradual loss ofperipheral vision. In other cases, early degeneration of thecone cells in themacula occurs, leading to a loss ofcentral acuity. In some cases, thefoveal vision is spared, leading to "doughnut vision"; central and peripheral vision are intact, but anannulus exists around the central region in whichvision is impaired.[citation needed]
| Type | Freq[9] | Gene locus | Gene | Protein | Function | Size (AA) | UniProt | OMIM |
|---|---|---|---|---|---|---|---|---|
| USH1B | 39–55% | 11q13.5 | MYO7A | Myosin VIIA | Motor protein | 2215 | Q13402 | 276900 |
| USH1C | 6–7% | 11p15.1-p14 | USH1C | Harmonin | PDZ-domain protein | 552 | Q9Y6N9 | 276904 |
| USH1D | 19–35% | 10q21-q22 | CDH23 | Cadherin 23 | Cell adhesion | 3354 | Q9H251 | 601067 |
| USH1E | rare | 21q21 | ? | ? | ? | ? | ? | 602097 |
| USH1F | 11–19% | 10q11.2-q21 | PCDH15 | Protocadherin 15 | Cell adhesion | 1955 | Q96QU1 | 602083 |
| USH1G | 7% | 17q24-q25 | USH1G | SANS | Scaffold protein | 461 | Q495M9 | 606943 |
| USH2A | 80% | 1q41 | USH2A | Usherin | Transmembrane linkage | 5202 | O75445 | 276901 |
| USH2C | 15% | 5q14.3-q21.1 | GPR98 | VLGR1b | Very largeGPCR | 6307 | Q8WXG9 | 605472 |
| USH2D | 5% | 9q32-q34 | DFNB31 | Whirlin | PDZ-domain protein | 907 | Q9P202 | 611383 |
| USH3A | 100% | 3q21-q25 | CLRN1 | Clarin-1 | Synaptic shaping | 232 | P58418 | 276902 |
Usher syndrome is inherited in anautosomal recessive pattern. Several genes have been associated with Usher syndrome usinglinkage analysis of patient families (Table 1) andDNA sequencing of the identifiedloci.[10][11] A mutation in any one of these genes is likely to result in Usher syndrome.[citation needed]
The clinical subtypes Usher I and II are associated with mutations in any one of six (USH1B-G) and three (USH2A, C-D) genes, respectively, whereas only one gene,USH3A, has been linked to Usher III so far. Two other genes,USH1A andUSH2B, were initially associated with Usher syndrome, butUSH2B has not been verified, and USH1A was incorrectly determined and does not exist.[12] Research in this area is ongoing.[citation needed]
Using interaction analysis techniques, the identified gene products could be shown to interact with one another in one or more largerprotein complexes. If one of the components is missing, this protein complex cannot fulfill its function in the living cell, and it probably comes to thedegeneration the same. The function of this protein complex has been suggested to participate in thesignal transduction or in thecell adhesion of sensory cells.[11]
A study shows that three proteins related to Usher syndrome genes (PCDH15,CDH23,GPR98) are also involved inauditory cortex development, in mouse and macaque. Their lack of expression induces a decrease in the number ofparvalbumininterneurons. Patients with mutations for these genes could have consequently auditory cortex defects.[13]
The progressive blindness of Usher syndrome results fromretinitis pigmentosa.[14][15] Thephotoreceptor cells usually start to degenerate from the outer periphery to the center of theretina, including themacula. The degeneration is usually first noticed as night blindness (nyctalopia); peripheral vision is gradually lost, restricting the visual field (tunnel vision), which generally progresses to complete blindness. The qualifierpigmentosa reflects the fact that clumps of pigment may be visible by anophthalmoscope in advanced stages of degeneration.[16]
The hearing impairment associated with Usher syndrome is caused by damaged hair cells in thecochlea of theinner ear inhibiting electrical impulses from reaching the brain. It is a form ofdysacusis.[citation needed]
Since Usher syndrome is incurable at present, it is helpful to diagnose children well before they develop the characteristic night blindness. Some preliminary studies have suggested as many as 10% of children with congenital severe to profound deafness may have Usher syndrome.[1] However, a misdiagnosis can have bad consequences.[citation needed]
The simplest approach to diagnosing Usher syndrome is to test for the characteristicchromosomal mutations. An alternative approach iselectroretinography, although this is often disfavored for children since its discomfort can also make the results unreliable.[1] Parental consanguinity is a significant factor in diagnosis. Usher syndrome I may be indicated if the child is profoundly deaf from birth and especially slow in walking.[citation needed]
Thirteen other syndromes may exhibit signs similar to Usher syndrome, includingAlport syndrome,Alström syndrome,Bardet–Biedl syndrome,Cockayne syndrome,spondyloepiphyseal dysplasia congenita,Flynn–Aird syndrome,Friedreich ataxia,Hurler syndrome (MPS-1),Kearns–Sayre syndrome (CPEO),Norrie syndrome,osteopetrosis (Albers–Schonberg disease),Refsum disease (phytanic acid storage disease) andZellweger syndrome (cerebrohepatorenal syndrome).[citation needed]
Although Usher syndrome has been classified clinically in several ways,[17][15][18] the prevailing approach is to classify it into three clinical sub-types called Usher I, II and III in order of decreasing severity of deafness.[14][16] Although it was previously believed that there was an Usher syndrome type IV, researchers at theUniversity of Iowa recently[when?] confirmed that there is no USH type IV.[citation needed] As described below, these clinical subtypes may be further subdivided by the particular gene mutated; people with Usher I and II may have any one of six and three genes mutated, respectively, whereas only one gene has been associated with Usher III. The function of these genes is still poorly understood.[citation needed]
Usher syndrome is a variable condition; the degree of severity is not tightly linked to whether it is Usher I, II, or III. For example, someone with type III may be unaffected in childhood but go on to develop a profound hearing loss and a very significant loss of sight by early-to-mid adulthood. Similarly, someone with type I, who is therefore profoundly deaf from birth, may keep good central vision until the sixth decade of life or even beyond. People with type II, who have useful hearing with a hearing aid, can experience a wide range of severity of the RP. Some may maintain good reading vision into their 60s, while others cannot see to read while still in their 40s.[citation needed]
Since Usher syndrome is inherited in anautosomal recessive pattern, both males and females are equally likely to inherit it.Consanguinity of the parents is a risk factor.[citation needed]
Since Usher syndrome results from the loss of a gene,gene therapy that adds the proper protein back ("gene replacement") may alleviate it, provided the added protein becomes functional. Recent studies ofmouse models have shown one form of the disease—that associated with a mutation inmyosin VIIa—can be alleviated by replacing the mutant gene using alentivirus.[19] However, some of the mutated genes associated with Usher syndromeencode very large proteins—most notably, theUSH2A andGPR98proteins, which have roughly 6000amino-acid residues. Scientists have successfully treated mice with Usher syndrome type 1C, which has a relatively small affected gene.[20]
Usher syndrome is responsible for the majority ofdeafblindness.[21] It occurs in roughly 1 in 23,000 people in theUnited States,[22] 1 in 28,000 in Norway,[3] and 1 in 12,500 in Germany.[2] People with Usher syndrome represent roughly one-sixth of people withretinitis pigmentosa.[16]
Usher syndrome is named after the Scottish ophthalmologistCharles Usher, who examined thepathology andtransmission of this illness in 1914 based on 69 cases.[23] However, it was first described in 1858 byAlbrecht von Gräfe, a pioneer of modernophthalmology.[24] He reported the case of a deaf patient withretinitis pigmentosa, who had two brothers with the same symptoms. Three years later, one of his students,Richard Liebreich, examined the population of Berlin for disease patterns of deafness with retinitis pigmentosa.[25] Liebreich noted Usher syndrome to be recessive since the cases of blind-deafness combinations occurred particularly in the siblings of blood-related marriages or in families with patients in different generations. His observations supplied the first proofs for the coupled transmission of blindness and deafness since no isolated cases of either could be found in the family trees.[citation needed]
Animal models of this human disease (such asknockout mice andzebrafish) have been developed recently[when?] to study the effects of these gene mutations and to test potential cures for Usher syndrome.[citation needed]