Cellular and molecular origin of circumpapillary dysgenesis of the pigment epithelium.
OBJECTIVE
We studied clinical phenotyping and TEAD1 expression in mice and humans to gain a better understanding of the primary origin in the pathogenesis of circumpapillary dysgenesis of the pigment epithelium.


METHODS
Observational case series and experimental study.


METHODS
Three female patients from an affected family were included for phenotypic study. Mice and human tissues were used for biochemistry and immunohistochemistry studies.


METHODS
We performed genetic analyses and longitudinal clinical, imaging, and electrophysiologic studies in a 3-generation family. Western blotting and immunohistochemistry were used to detect TEAD1 expression in mice and human retinal tissues.


METHODS
Autofluorescence and optical coherence tomography (OCT) imaging were compared and reviewed from 3 patients. TEAD1 expression was compared in different tissues from mice and human samples.


RESULTS
A point mutation at T1261 in TEAD1 was detected in the mother. Autofluorescence and OCT imaging studies revealed choroid is involved earlier than retinal pigment epithelium (RPE). From immunoblot analysis, we discovered that TEAD1 and its cofactors YAP65 and FOXA2 are expressed in the choroid. Immunohistochemical analysis on frozen sections of mouse retina supports immunoblot results.


CONCLUSIONS
The primary cellular origin of circumpapillary dysgenesis of the pigment epithelium is within the choroid instead of the pigment epithelium. The loss of the RPE and photoreceptors in later stages of the disease is a secondary consequence of choroidal degeneration. Studies of the downstream targets of TEAD1 in choroidal cells will provide promising new research opportunities for the development of treatments for choroidal diseases.


BACKGROUND
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Tosi
Joaquin
J
Bernard and Shirlee Brown Glaucoma Laboratory, Department of Pathology and Cell Biology, Columbia University, 160 Fort Washington Ave., New York, NY 10032, USA.
Janisch
Kerstin M
KM
Wang
Nan-Kai
NK
Kasanuki
J Mie
JM
Flynn
John T
JT
Lin
Chyuan-Sheng
CS
Tsang
Stephen H
SH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002675:Child, Preschool; D015862:Choroid Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004596:Electroretinography; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D055213:Retinal Pigment Epithelium / Q000002:abnormalities* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000091262:TEA Domain Transcription Factors; D041623:Tomography, Optical Coherence; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C496502:FOXA2 protein, human; C496503:Foxa2 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; C083215:Tead1 protein, mouse; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; D051542:Hepatocyte Nuclear Factor 3-beta