title: The Usher 1B protein, MYO7A, is required for normal localization and function of the visual retinoid cycle enzyme, RPE65.
abstract: Mutations in the MYO7A gene cause a deaf-blindness disorder, known as Usher syndrome 1B.  In the retina, the majority of MYO7A is in the retinal pigmented epithelium (RPE), where many of the reactions of the visual retinoid cycle take place.  We have observed that the retinas of Myo7a-mutant mice are resistant to acute light damage. In exploring the basis of this resistance, we found that Myo7a-mutant mice have lower levels of RPE65, the RPE isomerase that has a key role in the retinoid cycle.  We show for the first time that RPE65 normally undergoes a light-dependent translocation to become more concentrated in the central region of the RPE cells.  This translocation requires MYO7A, so that, in Myo7a-mutant mice, RPE65 is partly mislocalized in the light.  RPE65 is degraded more quickly in Myo7a-mutant mice, perhaps due to its mislocalization, providing a plausible explanation for its lower levels.  Following a 50-60% photobleach, Myo7a-mutant retinas exhibited increased all-trans-retinyl ester levels during the initial stages of dark recovery, consistent with a deficiency in RPE65 activity.  Lastly, MYO7A and RPE65 were co-immunoprecipitated from RPE cell lysate by antibodies against either of the proteins, and the two proteins were partly colocalized, suggesting a direct or indirect interaction.  Together, the results support a role for MYO7A in the translocation of RPE65, illustrating the involvement of a molecular motor in the spatiotemporal organization of the retinoid cycle in vision.
authors.affiliation: Jules Stein Eye Institute and Department of Neurobiology, UCLA School of Medicine, University of California-Los Angeles, 200 Stein Plaza, Los Angeles, CA 90095, USA.
authors.forename: Vanda S
authors.initials: VS
authors.lastname: Lopes
authors.forename: Daniel
authors.initials: D
authors.lastname: Gibbs
authors.forename: Richard T
authors.initials: RT
authors.lastname: Libby
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Darcy L
authors.initials: DL
authors.lastname: Welch
authors.forename: Concepción
authors.initials: C
authors.lastname: Lillo
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Roxana A
authors.initials: RA
authors.lastname: Radu
authors.forename: Karen P
authors.initials: KP
authors.lastname: Steel
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008027:Light / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000235:genetics / Q000528:radiation effects; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology; D052245:Usher Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D005136:Eye Proteins; C000631455:MYO7A protein, human; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D009218:Myosins