PMID- 24644049
OWN - NLM
STAT- MEDLINE
DCOM- 20140520
LR  - 20211021
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 55
IP  - 4
DP  - 2014 Apr 17
TI  - The Rpe65 rd12 allele exerts a semidominant negative effect on vision in mice.
PG  - 2500-15
LID - 10.1167/iovs.13-13574 [doi]
AB  - PURPOSE: The rd12 mouse was reported as a recessively inherited Rpe65 mutation. 
      We asked if the rd12 mutation resides in Rpe65 and how the mutation manifests 
      itself. METHODS: A complementation test was performed by mating Rpe65(KO) (KO/KO) 
      and rd12 mice together to determine if the rd12 mutation is in the Rpe65 gene. 
      Visual function of wild-type (+/+), KO/+, rd12/+, KO/KO, rd12/rd12, and KO/rd12 
      mice was measured by optokinetic tracking (OKT) and ERG. Morphology was assessed 
      by retinal cross section. qRT-PCR quantified Rpe65 mRNA levels. Immunoblotting 
      measured the size and level of RPE65 protein. Rpe65 mRNA localization was 
      visualized with RNA fluorescence in situ hybridization (FISH). Fractions of Rpe65 
      mRNA-bound proteins were separated by linear sucrose gradient fractionation. 
      RESULTS: The KO and rd12 alleles did not complement. The rd12 allele induced a 
      negative semidominant effect on visual function; OKT responses became 
      undetectable 120 days earlier in rd12/rd12 mice compared with KO/KO mice. rd12/+ 
      mice lost approximately 21% visual acuity by P210. rd12/rd12 mice had fewer cone 
      photoreceptor nuclei than KO/KO mice at P60. rd12/rd12 mice expressed 71% +/+ 
      levels of Rpe65 mRNA, but protein was undetectable. Mutant mRNA was appropriately 
      spliced, exported to the cytoplasm, trafficked, and contained no other coding 
      mutation aside from the known nonsense mutation. Mutant mRNA was enriched on 
      ribosome-free messenger ribonucleoproteins (mRNPs), whereas wild-type mRNA was 
      enriched on actively translating polyribosomes. CONCLUSIONS: The rd12 lesion is 
      in Rpe65. The rd12 mutant phenotype inherits in a semidominant manner. The 
      effects of the mutant mRNA on visual function may result from inefficient binding 
      to ribosomes for translation.
FAU - Wright, Charles B
AU  - Wright CB
AD  - Department of Ophthalmology, School of Medicine, Emory University, Atlanta, 
      Georgia, United States.
FAU - Chrenek, Micah A
AU  - Chrenek MA
FAU - Feng, Wei
AU  - Feng W
FAU - Getz, Shannon E
AU  - Getz SE
FAU - Duncan, Todd
AU  - Duncan T
FAU - Pardue, Machelle T
AU  - Pardue MT
FAU - Feng, Yue
AU  - Feng Y
FAU - Redmond, T Michael
AU  - Redmond TM
FAU - Boatright, Jeffrey H
AU  - Boatright JH
FAU - Nickerson, John M
AU  - Nickerson JM
LA  - eng
GR  - R01 EY016470/EY/NEI NIH HHS/United States
GR  - P30EY006360/EY/NEI NIH HHS/United States
GR  - Z01EY000444/EY/NEI NIH HHS/United States
GR  - T32 EY007092/EY/NEI NIH HHS/United States
GR  - R01EY014026/EY/NEI NIH HHS/United States
GR  - R01NS070526/NS/NINDS NIH HHS/United States
GR  - R01 NS070526/NS/NINDS NIH HHS/United States
GR  - R01EY021592/EY/NEI NIH HHS/United States
GR  - T32EY007092/EY/NEI NIH HHS/United States
GR  - P30 EY006360/EY/NEI NIH HHS/United States
GR  - R01 EY014026/EY/NEI NIH HHS/United States
GR  - R01 EY021592/EY/NEI NIH HHS/United States
GR  - R01 EY016435/EY/NEI NIH HHS/United States
GR  - Z01 EY000444/Intramural NIH HHS/United States
GR  - R01EY016470/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140417
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (Codon, Nonsense)
RN  - 63231-63-0 (RNA)
RN  - EC 3.1.1.64 (retinoid isomerohydrolase)
RN  - EC 5.2.- (cis-trans-Isomerases)
SB  - IM
MH  - Alleles
MH  - Animals
MH  - *Codon, Nonsense
MH  - Disease Models, Animal
MH  - Electroretinography
MH  - Genotype
MH  - Immunoblotting
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Phenotype
MH  - Photoreceptor Cells, Vertebrate/*metabolism
MH  - RNA/*genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Retinal Degeneration/*genetics/metabolism/physiopathology
MH  - *Visual Acuity
MH  - cis-trans-Isomerases/biosynthesis/*genetics
PMC - PMC3993890
OTO - NOTNLM
OT  - RPE65
OT  - rd12
OT  - visual cycle
EDAT- 2014/03/20 06:00
MHDA- 2014/05/21 06:00
PMCR- 2014/10/01
CRDT- 2014/03/20 06:00
PHST- 2014/03/20 06:00 [entrez]
PHST- 2014/03/20 06:00 [pubmed]
PHST- 2014/05/21 06:00 [medline]
PHST- 2014/10/01 00:00 [pmc-release]
AID - iovs.13-13574 [pii]
AID - 10.1167/iovs.13-13574 [doi]
PST - epublish
SO  - Invest Ophthalmol Vis Sci. 2014 Apr 17;55(4):2500-15. doi: 10.1167/iovs.13-13574.