Usher syndrome: a review of the clinical phenotype, genes and therapeutic strategies

Abstract

Usher syndrome (USH) is the most common cause of deaf–blindness in humans. It is a clinically and genetically heterogeneous disorder, for which 10 causative genes have been identified so far. The USH genes encode a number of structurally and functionally distinct proteins that form complexes in the inner ear and retina essential for hearing and vision. Animal studies have indicated that the hearing loss associated with USH mainly results from abnormal development of the hair bundle, the mechanoreceptive organelle of the sensory hair cells. In contrast, the molecular and cellular mechanisms underlying the USH visual impairment remain unclear. Although a cure for USH is not yet available, a host of promising therapeutic studies have made progress toward developing an effective treatment for the retinal defects associated with USH. This review provides an outline of the genes and proteins underlying USH, their interactions and functions in the inner ear and retina, and the therapeutic strategies that are under investigation as potential treatments for this disease.

Keywords:

• gene therapy
• hair cell
• hearing loss
• photoreceptor
• retinitis pigmentosa
• stereocilia
• Usher syndrome

Acknowledgements

We would like to acknowledge the National Institute for Health Research UK (Moorfields Eye Hospital and UCL Institute of Ophthalmology Biomedical Research Centre) and the Academy of Medical Sciences.

Financial & competing interests disclosure

The authors were supported by the National Institute for Health Research and the Academy of Medical Sciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Usher syndrome (USH) is characterized by the combination of sensorineural hearing loss with retinitis pigmentosa. It is categorized into three clinical subtypes (USH1, USH2 and USH3) according to severity of hearing loss and the presence or absence of vestibular dysfunction.

• It is an autosomal recessive disorder and 10 causative genes have been identified so far: MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2, USH2A, GPR98, WHRN, and CLRN1.

• A number of mouse and zebrafish models have been described for the USH genes that have characteristic hair cell stereociliary dysmorphology and mimic the hearing impairment observed in USH patients. However, only a few show retinal defects.

• The proteins encoded by the USH genes have been found to form multiprotein complexes in the inner ear and retina, where they are thought to be involved in hair bundle development, mechanotransduction, protein transport and synaptogenesis.

• A range of therapeutic studies have mostly focused on treating the retinitis pigmentosa, and strategies have included viral vector gene delivery, cell transplantation, genome-editing and the use of read-through drugs and antisense oligonucleotides.