Usher syndrome

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**Usher syndrome**
*Classifications and external resources*
OMIM	276900 276901
DiseasesDB	13611

Usher syndrome (sometimes referred to as "Usher's syndrome") is a genetic disease causing deaf-blindness. It is essentially progressive retinitis pigmentosa combined with congenital hearing impairment. It is inherited in an autosomal recessive pattern. While this is a rare genetic condition, it represents the major cause of syndromic deafness with blindness.

1 Signs and Symptoms
2 History and Cause
3 References
4 External links

[edit] Signs and Symptoms

The Usher syndrome is defined as innate reciprocal congenital deafness and progressing loss of vision due to retinitis pigmentosa. Usually the photoreceptors start to degenerate from the outer periphery to the center of the retina including the macula. For the patient the RP is noticeable in the beginning with night blindness (nyctalopia), proceeding into a slow, progressive restriction of the visual field (tunnel vision), which usually leads in a later stage to complete blindness. The hearing impairment with the Usher syndrome is essentially based on a damage of the hair cells in the cochlea of the inner ear. It is usually present from birth in the form of deafness or middle to high-grade hearing impairment.

On the basis of the severity of symptoms, the Usher syndrome was divided into three types: I, II and III. Children with type I syndrome are born profoundly deaf, and eyesight usually begins degrading after the first decade of life, beginning with night-blindness. They also experience degrading tunnel vision. If identified at a young age, children usually receive a cochlear implant, and some then use spoken language. Many use sign language. When vision loss is severe or when one is blind, one must use tactile signing. Problems with balance are present in people with Usher I and sometimes Usher III, due to the failure of the hair cells of the inner ear. Type II children are hard-of-hearing with stable hearing throughout their lives. Changes in sight in type II cases usually begin later, sometimes only becoming noticeable after the second decade of life. In the type III syndrome, hearing loss as well as retinitis pigmentosa can occur later in life. Hearing loss in Usher III is progressive.

[edit] History and Cause

Usher syndrome was probably described for the first time in 1858 by Albrecht von Gräfe, a pioneer of modern ophthalmology ^[1]. He reported the case of a deaf patient with retinitis pigmentosa, who had two brothers with the same symptoms. A short time later, one of his students, Richard Liebreich, examined the population of Berlin for disease pattern of deafness with retinitis pigmentosa ^[2]. He already stressed the recessive nature of this illness, since the cases of blind-deafness combinations occurred particularly in the siblings of blood-related marriages or in families with patients in different generations. Additionally his observations supplied the first proofs for the coupled transmission of the disease, since no cases of isolated blindness or deafness in the family trees could be found.

Finally the disease pattern was designated after the British ophthalmologist Charles Usher, who examined the pathology and transmission of this illness in 1914 on the basis of 69 cases ^[3].

Known Usher syndrome subtypes (without USH1A).
Usher-Type	Gene locus	Gene	Protein	Function	OMIM
1B	11q13.5	MYO7A	Myosin VIIA	Motor protein	276900
1C	11p15.1-p14	USH1C	Harmonin	Scaffold protein	276904
1D	10q21-q22	CDH23	Cadherin 23	Cell adhesion	601067
1E	21q21	?	?	?	602097
1F	10q11.2-q21	PCDH15	Protocadherin 15	Cell adhesion	602083
1G	17q24-q25	USH1G	SANS	Scaffold protein	606943
2A	1q41	USH2A	Usherin	?	276901
2B	3p23-p24.2	SLC4A7	NBC-3	Cotransporter of ions	276905
2C	5q14.3-q21.1	VLGR1	VLGR1b	Very large GPCR	605472
3A	3q21-q25	USH3A	Clarin-1	?	276902
3B	20q	?	?	?

With the advancement of the scientific methods, the genetic heterogeneity of the Usher syndrome was described toward the end of the 20th century. Using linkage analysis of patient families several independent loci on different chromosomes were identified (see table), in whom hereditary defects, which cause the Usher syndrome, were found. With the help of these loci the illness was divided in twelve subtypes (USH1A-G, USH2A-C, USH3A). In nine cases the concerned gene could be found by sequencing the candidate genes in these locations ^[4] ^[5]. On the other hand, it could be shown that one Usher subtype - USH1A on chromosome locus 14q32 - was incorrectly determined and does not exist ^[6].

Using interaction analysis techniques it could be shown that the identified gene products interact with one another in one or more larger protein complexes. If one of the components is missing, this protein complex cannot fulfill its function in the living cell and it probably comes to the degeneration the same. The function of this protein complex has been suggested to participate in the signal transduction or in the cell adhesion of sensory cell ^[5].

[edit] Usher syndrome I

Usher syndrome is inherited in an autosomal recessive pattern.

Worldwide, the estimated prevalence of Usher syndrome type I is 3 to 6 per 100,000 people in the general population.

Mutations in the CDH23, MYO7A, PCDH15, Usher 1C (also known as Harmonin), and USH1G (now identified as SANS) genes cause Usher syndrome type I. Usher syndrome type I can be caused by mutations in one of several different genes. These genes function in the development and maintenance of inner 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 the retinal pigmented epithelium. Mutations that affect the normal function of these genes can result in retinitis pigmentosa and vision loss.

[edit] Usher syndrome II

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.

Mutations in the MASS1 (also called VLGR1) and USH2A genes cause Usher syndrome type II. Usher syndrome type II may be caused by mutations in any of three different genes, two of which have been identified to date. These genes are called USH2A and MASS1. Usherin, the protein made by the USH2A gene, is located in 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 precise function of the protein made by the MASS1 gene is not yet known.

[edit] Usher syndrome III

The frequency of Usher syndrome type III is highest in the Finnish population, but it has been noted rarely in a few other ethnic groups.

Mutations in the USH3A gene cause Usher syndrome type III. Usher syndrome type III can be caused by mutations in one of at least two genes, only one of which (USH3A) has been identified. The USH3A gene makes a protein that is important for the development and maintenance of the inner ear and retina. The protein's function in these structures, and its role in hearing and vision loss, have not yet been fully explained.

[edit] References

^ A. von Graefe: Exceptionelles Verhalten des Gesichtsfeldes bei Pigmententartung der Netzhaut. Archiv für Ophthalmologie 1858; 4: 250-253
^ R. Liebreich: Abkunft aus Ehen unter Blutsverwandten als Grund von Retinitis pigmentosa. Dtsch.Klin. 1861; 13: 53
^ C. Usher: On the inheritance of Retinitis pigmentosa with notes of cases. Roy.Lond.Ophthalmol.Hosp.Rep. 1914; 19: 130-236
^ C. Petit: Usher syndrome: from genetics to pathogenesis. Annu.Rev.Genomics Hum.Genet. 2001 (2): 271-297 PMID 11701652
^ ^a ^b J. Reiners et al.: Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Exp Eye Res. 2006;83(1):97-119 PMID 16545802
^ S. Gerber et al.: USH1A: Chronicle of a Slow Death. Am J Hum Genet. 2006;78(2):357-9. PMID 16400615