PMID- 28903150
OWN - NLM
STAT- MEDLINE
DCOM- 20170922
LR  - 20180307
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Linking)
VI  - 58
IP  - 11
DP  - 2017 Sep 1
TI  - Crx-L253X Mutation Produces Dominant Photoreceptor Defects in TVRM65 Mice.
PG  - 4644-4653
LID - 10.1167/iovs.17-22075 [doi]
AB  - Purpose: The cone-rod homeobox (CRX) transcription factor is essential for
      photoreceptor gene expression, differentiation, and survival. Human CRX mutations
      can cause dominant retinopathies of varying onset and phenotype severity. In
      animal models, dominant frameshift Crx mutations introduce a premature
      termination codon (PTC), producing inactive truncated proteins that interfere
      with normal CRX function. Previously, a mutant mouse, TVRM65, was reported to
      carry a recessive late PTC mutation, Crx-L253X. More detailed phenotype analysis 
      of the pathogenicity of Crx-L253X sheds new light on the variability of
      CRX-linked diseases. Methods: Homozygous (L253X/X); heterozygous (L253X/+);
      Crx-/- and control C57BL/6J (WT) mice were analyzed at various ages for changes
      in retinal function (ERG), morphology (histology) and photoreceptor gene
      expression (qRT-PCR). Results: At 1 month, L253X/X mice lack visual function,
      show greater reductions in retinal thickness, and distinct gene expression
      changes relative to Crx-/-, suggesting that the phenotype of L253X/X is more
      severe than Crx-/-. L253X/+ mice have reduced rod/cone function, but normal
      retinal morphology at all ages tested. qRT-PCR assays described a complex
      phenotype in which both developing and mature photoreceptors are unable to
      maintain proper gene expression. L253X mRNA/protein is overexpressed relative to 
      normal Crx, suggesting a pathogenic mechanism similar to early PTC mutations.
      However, the overexpression is less pronounced, correlating with a relatively
      mild dominant phenotype. Conclusions: The L253X mouse provides a valuable model
      for CRX-associated retinopathy. The pathogenicity of CRX frameshift mutations
      depends on the position of the PTC, which in turn determines the degree of mutant
      mRNA/protein overproduction.
FAU - Ruzycki, Philip A
AU  - Ruzycki PA
AD  - Molecular Genetics and Genomics Graduate Program, Division of Biology &
      Biomedical Sciences, Washington University, St. Louis, Missouri, United States.
AD  - Department of Ophthalmology and Visual Sciences, Washington University, St.
      Louis, Missouri, United States.
FAU - Linne, Courtney D
AU  - Linne CD
AD  - Department of Ophthalmology and Visual Sciences, Washington University, St.
      Louis, Missouri, United States.
FAU - Hennig, Anne K
AU  - Hennig AK
AD  - Department of Ophthalmology and Visual Sciences, Washington University, St.
      Louis, Missouri, United States.
FAU - Chen, Shiming
AU  - Chen S
AD  - Molecular Genetics and Genomics Graduate Program, Division of Biology &
      Biomedical Sciences, Washington University, St. Louis, Missouri, United States.
AD  - Department of Ophthalmology and Visual Sciences, Washington University, St.
      Louis, Missouri, United States.
AD  - Department of Developmental Biology, Washington University, St. Louis, Missouri, 
      United States.
LA  - eng
GR  - P30 EY002687/EY/NEI NIH HHS/United States
GR  - R01 EY012543/EY/NEI NIH HHS/United States
GR  - R01 EY025272/EY/NEI NIH HHS/United States
GR  - T32 EY013360/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (Codon, Nonsense)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Trans-Activators)
RN  - 0 (cone rod homeobox protein)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Codon, Nonsense/*genetics
MH  - Disease Models, Animal
MH  - Electroretinography
MH  - Female
MH  - *Frameshift Mutation
MH  - Gene Expression Regulation/physiology
MH  - *Genes, Dominant
MH  - Homeodomain Proteins/*genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Mutant Strains
MH  - Photoreceptor Cells, Vertebrate/*pathology
MH  - RNA, Messenger/genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Retina/physiopathology
MH  - Retinal Degeneration/*genetics/pathology
MH  - Trans-Activators/*genetics
PMC - PMC5597032
EDAT- 2017/09/14 06:00
MHDA- 2017/09/25 06:00
CRDT- 2017/09/14 06:00
PHST- 2017/09/14 06:00 [entrez]
PHST- 2017/09/14 06:00 [pubmed]
PHST- 2017/09/25 06:00 [medline]
AID - 2654114 [pii]
AID - 10.1167/iovs.17-22075 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2017 Sep 1;58(11):4644-4653. doi:
      10.1167/iovs.17-22075.