title: Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism.
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.
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. jacobsos@mail.med.upenn.edu
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.forename: Leigh M
authors.initials: LM
authors.lastname: Gardner
authors.forename: Haydn M
authors.initials: HM
authors.lastname: Prosser
authors.forename: Monalisa
authors.initials: M
authors.lastname: Mishra
authors.forename: N Torben
authors.initials: NT
authors.lastname: Bech-Hansen
authors.forename: Waldo
authors.initials: W
authors.lastname: Herrera
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Liu
authors.forename: William J
authors.initials: WJ
authors.lastname: Kimberling
authors.forename: Karen P
authors.initials: KP
authors.lastname: Steel
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics; D002648:Child; D004398:Dyneins / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology*; D010857:Pigment Epithelium of Eye / Q000378:metabolism / Q000473:pathology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D052245:Usher Syndromes / Q000235:genetics* / Q000473:pathology*
chemical_list: C417525:ADGRV1 protein, human; C498835:CDHR15, human; C448939:CRB1 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; C000631455:MYO7A protein, human; D008565:Membrane Proteins; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; C112735:USH2A protein, human; D009218:Myosins; D004398:Dyneins