Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism

Samuel G. Jacobson, Artur V. Cideciyan, Tomas S. Aleman, Alexander Sumaroka, Alejandro J. Roman, Leigh M. Gardner, Haydn M. Prosser, Monalisa Mishra, N. Torben Bech-Hansen, Waldo Herrera, Sharon B. Schwartz, Xue Zhong Liu, William J. Kimberling, Karen P. Steel, David S. Williams

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2405-2415
Number of pages11
JournalHuman molecular genetics
Volume17
Issue number15
DOIs
StatePublished - Aug 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Jacobson, S. G., Cideciyan, A. V., Aleman, T. S., Sumaroka, A., Roman, A. J., Gardner, L. M., Prosser, H. M., Mishra, M., Bech-Hansen, N. T., Herrera, W., Schwartz, S. B., Liu, X. Z., Kimberling, W. J., Steel, K. P., & Williams, D. S. (2008). Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism. Human molecular genetics, 17(15), 2405-2415. https://doi.org/10.1093/hmg/ddn140