Human Molecular Genetics Advance Access originally published online on May 7, 2008
Human Molecular Genetics 2008 17(15):2405-2415; doi:10.1093/hmg/ddn140
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Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism
1 Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA 2 The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK 3 Departments of Ophthalmology and Neurobiology, UCLA School of Medicine, Jules Stein Eye Institute, Los Angeles, CA, USA 4 Department of Medical Genetics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada 5 Department of Otolaryngology, University of Miami, Miami, FL, USA 6 Usher Syndrome Center, Boys Town National Research Hospital, Omaha, NE, USA
* To whom correspondence should be addressed at: Scheie Eye Institute, University of Pennsylvania, 51 N. 39th Street, Philadelphia, PA 19104, USA. Tel: +1 2156629981; Fax: +1 2156629388; Email: jacobsos{at}mail.med.upenn.edu
Received March 19, 2008; Accepted April 29, 2008
Usher syndrome (USH) is a genetically heterogeneous group of autosomal recessive deaf-blinding disorders. Pathophysiology leading to the blinding retinal degeneration in USH is uncertain. There is evidence for involvement of the photoreceptor cilium, photoreceptor synapse, the adjacent retinal pigment epithelium (RPE) cells, and the Crumbs protein complex, the latter implying developmental abnormalities in the retina. Testing hypotheses has been difficult in murine USH models because most do not show a retinal degeneration phenotype. We defined the retinal disease expression in vivo in human USH using optical imaging of the retina and visual function. In MYO7A (USH1B), results from young individuals or those at early stages indicated the photoreceptor was the first detectable site of disease. Later stages showed photoreceptor and RPE cell pathology. Mosaic retinas in Myo7a-deficient shaker1 mice supported the notion that the mutant photoreceptor phenotype was cell autonomous and not secondary to mutant RPE. Humans with PCDH15 (USH1F), USH2A or GPR98 (USH2C) had a similar retinal phenotype to MYO7A (USH1B). There was no evidence of photoreceptor synaptic dysfunction and no dysplastic phenotype as in CRB1 (Crumbs homologue1) retinopathy. The results point to the photoreceptor cell as the therapeutic target for USH treatment trials, such as MYO7A somatic gene replacement therapy.
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