PMID- 28041994
OWN - NLM
STAT- MEDLINE
DCOM- 20170529
LR  - 20181113
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Print)
IS  - 0002-9440 (Linking)
VI  - 187
IP  - 3
DP  - 2017 Mar
TI  - A Dominant Mutation in Rpe65, D477G, Delays Dark Adaptation and Disturbs the 
      Visual Cycle in the Mutant Knock-In Mice.
PG  - 517-527
LID - S0002-9440(16)30521-1 [pii]
LID - 10.1016/j.ajpath.2016.11.004 [doi]
AB  - RPE65 is an indispensable component of the retinoid visual cycle in vertebrates, 
      through which the visual chromophore 11-cis-retinal (11-cis-RAL) is generated to 
      maintain normal vision. Various blinding conditions in humans, such as Leber 
      congenital amaurosis and retinitis pigmentosa (RP), are attributed to either 
      homozygous or compound heterozygous mutations in RPE65. Herein, we investigated 
      D477G missense mutation, an unprecedented dominant-acting mutation of RPE65 
      identified in patients with autosomal dominant RP. We generated a D477G knock-in 
      (KI) mouse and characterized its phenotypes. Although RPE65 protein levels were 
      decreased in heterozygous KI mice, their scotopic, maximal, and photopic 
      electroretinography responses were comparable to those of wild-type (WT) mice in 
      stationary condition. As shown by high-performance liquid chromatography 
      analysis, levels of 11-cis-RAL in fully dark-adapted heterozygous KI mice were 
      similar to that in WT mice. However, kinetics of 11-cis-RAL regeneration after 
      light exposure were significantly slower in heterozygous KI mice compared with WT 
      and RPE65 heterozygous knockout mice. Furthermore, heterozygous KI mice exhibited 
      lower A-wave recovery compared with WT mice after photobleaching, suggesting a 
      delayed dark adaptation. Taken together, these observations suggest that D477G 
      acts as a dominant-negative mutant of RPE65 that delays chromophore regeneration. 
      The KI mice provide a useful model for further understanding of the pathogenesis 
      of RP associated with this RPE65 mutant and for the development of therapeutic 
      strategies.
CI  - Copyright (c) 2017 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Shin, Younghwa
AU  - Shin Y
AD  - Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma 
      City, Oklahoma.
FAU - Moiseyev, Gennadiy
AU  - Moiseyev G
AD  - Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma 
      City, Oklahoma.
FAU - Chakraborty, Dibyendu
AU  - Chakraborty D
AD  - Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma 
      City, Oklahoma.
FAU - Ma, Jian-Xing
AU  - Ma JX
AD  - Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma 
      City, Oklahoma. Electronic address: jian-xing-ma@ouhsc.edu.
LA  - eng
GR  - R01 EY018659/EY/NEI NIH HHS/United States
GR  - P30 GM122744/GM/NIGMS NIH HHS/United States
GR  - P20 GM104934/GM/NIGMS NIH HHS/United States
GR  - R01 EY012231/EY/NEI NIH HHS/United States
GR  - R01 EY019309/EY/NEI NIH HHS/United States
GR  - R01 EY016507/EY/NEI NIH HHS/United States
PT  - Journal Article
DEP - 20161230
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Opsins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Retinoids)
RN  - EC 3.1.1.64 (retinoid isomerohydrolase)
RN  - EC 5.- (Isomerases)
RN  - EC 5.2.- (cis-trans-Isomerases)
SB  - IM
MH  - Animals
MH  - Chromatography, High Pressure Liquid
MH  - Dark Adaptation/*genetics
MH  - Electroretinography
MH  - *Gene Knock-In Techniques
MH  - *Genes, Dominant
MH  - Heterozygote
MH  - Isomerases/metabolism
MH  - Mice, Mutant Strains
MH  - Models, Animal
MH  - Mutation/*genetics
MH  - Opsins/metabolism
MH  - Photobleaching
MH  - RNA, Messenger/genetics/metabolism
MH  - Regeneration
MH  - Retina/metabolism/pathology
MH  - Retinoids/metabolism
MH  - Visual Pathways/*metabolism
MH  - cis-trans-Isomerases/*genetics/metabolism
PMC - PMC5389371
EDAT- 2017/01/04 06:00
MHDA- 2017/05/30 06:00
PMCR- 2018/03/01
CRDT- 2017/01/03 06:00
PHST- 2016/09/05 00:00 [received]
PHST- 2016/11/01 00:00 [revised]
PHST- 2016/11/03 00:00 [accepted]
PHST- 2017/01/04 06:00 [pubmed]
PHST- 2017/05/30 06:00 [medline]
PHST- 2017/01/03 06:00 [entrez]
PHST- 2018/03/01 00:00 [pmc-release]
AID - S0002-9440(16)30521-1 [pii]
AID - 10.1016/j.ajpath.2016.11.004 [doi]
PST - ppublish
SO  - Am J Pathol. 2017 Mar;187(3):517-527. doi: 10.1016/j.ajpath.2016.11.004. Epub 
      2016 Dec 30.