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Molecular Basis

Usher Syndrome is inherited as an autosomal recessive trait which is clinically and genetically heterogeneous, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder each carry one copy of the altered gene but do not show signs and symptoms of the disorder. Some patients show abnormal organization of microtubules in the axoneme of their photoreceptors cells (connecting cilium), nasal ciliar cells and sperm cells, as well as widespread degeneration of the organ of Corti. USH was subdivided into three clinical types, namely USH1,USH2 and USH3 (US National Library of Medicine, 2007).

USH type 1

The most severe form of this disease, patients are deaf at birth and the onset of RP is pre-pubertal. USH1 patients exhibit severe dysfunction of the vestibular system which leads to a further subdivision of USH type 1 (Otterstedde et al., 2001).

Mutations in genes at six different loci cause Usher syndrome type I. Genes at five of these loci, MYO7A (USH1B), USH1C, CDH23 (USH1D), PCDH15 (USH1F), and USH1G have been identified. Molecular genetic testing is clinically available for MYO7A and PCDH15 mutations. Testing for mutations in all other genes associated with Usher type I is available on a research basis only.

USH type 2

It is characterized by a constant moderate to severe hearing impairment from birth on and RP can be diagnosed during puberty (Reisser et al.,2002).

Two genes known to be associated with Usher syndrome type II have been identified: USH2A accounts for 80% of type II cases and GPR98 (VLGR1) accounts for about 15% of type II cases. A third locus, USH2B, has been mapped, but the gene is not yet known and a fourth locus, USH2D, is postulated but unknown.

The gene USH2A has been found to produce the protein Usherin, which is responsible for the integrity f supportive tissue in the retina and inner ear. Clinical testing for mutation to the SH2A gene is available, which can be used to diagnose approximately 80% of people with Usher syndrome type II. Testing for mutations in GPR98 is available on a research basis only.

USH type 3

Differentiating Usher syndrome type III from types I and II can be difficult because of similar clinical manifestations. It is distinguished from USH1 and USH2 only by the later initiation of deafness combined with variable RP and vestibular dysfunction. In USH3 patients, the hearing impairment is progressive starting post-lingual and RP is diagnosed in most cases between the 2nd and 4th decade of life (Pakarinen et al., 1995; Petit, 2001).

Researchers speculate that Usher syndrome type III is caused by at least two genes, but only one gene (CLRN1) has been identified

So what’s happening at a molecular level?

The genes related to Usher syndrome provide instructions for making proteins that play important roles in normal hearing, balance, and vision. They function in the development and maintenance of hair cells, which are sensory cells in the inner ear that help transmit sound and motion signals to the brain. In the retina, these genes are also involved in determining the structure and function of light-sensing cells called rods and cones Most of the mutations responsible for Usher syndrome lead to a loss of hair cells in the inner ear and a gradual loss of rods and cones in the retina (Reiner, 2006). Degeneration of these sensory cells causes hearing loss, balance problems, and vision loss characteristic of this condition.

The proteins encoded by the Usher genes are members of protein classes with very different functions. Myosin VIIa is a motor protein, harmonin and SANS (scaffold protein containing ankyrin repeats and SAM domain) are scaffold proteins, cadherin 23 and protocadherin 15 are cell adhesion molecules and USH2A/usherin (isoform B) and VLGR1b (very large G-coupled protein receptor isoform b) are transmembrane proteins that could be involved in outside-in signaling (Kremer et al., 2006).

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