Journal Article10.1167/IOVS.13-12089
Mice with a targeted disruption of Slc4a11 model the progressive corneal changes of congenital hereditary endothelial dystrophy.
Sang Beom Han,Heng-Pei Ang,Rebekah Poh,Shyam S. Chaurasia,Gary S L Peh,Jun Liu,Donald T.H. Tan,Eranga N. Vithana,Jodhbir S. Mehta +8 more
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TL;DR: The authors' Slc4a11 KO mouse model successfully represents clinical manifestations of human CHED and was able to show chronological corneal progression for the first time in a knockout mouse model as well as renal abnormalities.
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Abstract: Purpose To establish an animal model of congenital hereditary endothelial dystrophy (CHED) using Slc4a11 knockout (KO) mice and evaluate the abnormalities in the cornea and kidney. Methods The Slc4a11 KO mouse model was generated by gene deletion. Corneal abnormalities were evaluated using slit-lamp photography, anterior segment optical coherence tomography (AS-OCT), immunohistochemistry, RT-PCR, corneal endothelial cell staining, and electron microscopy. The temporal corneal changes were also monitored. Histological and functional changes of the kidney were also evaluated. Results Successful knockout of the Slc4a11 gene was confirmed by immunohistochemistry and RT-PCR. Slit-lamp photography and AS-OCT showed progressive corneal edema. Increased corneal endothelial cell size with decreased corneal endothelial cell density was observed with increased age. Scanning electron microscopy also revealed progressive cell swelling and distortion of the hexagonal cell morphology with time. Transmission electron microscopy showed characteristic ultrastructural findings of CHED, including endothelial vacuolization, thickening of the Descemet membrane, disorganization of collagen fibril, deposition of amorphous material, and progression of these changes with age. Decreased urine osmolarity and electrolyte concentrations suggesting abnormality in water resorption were also detected. Conclusions Our Slc4a11 KO mouse model successfully represents clinical manifestations of human CHED. We were able to show chronological corneal progression for the first time in a knockout mouse model as well as renal abnormalities.
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Applications of Anterior Segment Optical Coherence Tomography in Cornea and Ocular Surface Diseases
TL;DR: This review will discuss the application of AS-OCT for diagnosis and management of various corneal and ocular surface disorders, and application of the device for research using human data and animal models.
Human SLC4A11 Is a Novel NH3/H+ Co-transporter
TL;DR: SLC4A11 is a novel NH3/H+ co-transporter, uncharacteristic of the SLC4 bicarbonate transporter family, and should be considered along with other NH3 transporters/channels when examining tissue nitrogen homeostasis.
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SLC4A11 and the Pathophysiology of Congenital Hereditary Endothelial Dystrophy.
Sangita P Patel,Mark D. Parker +1 more
TL;DR: Slc4a11-null-mouse models recapitulate the CHED disease phenotype, thus establishing a functional role for SLC4A11 in CHED, and future studies of the consequences of SLC3A11 dysfunction as well as further understanding of corneal endothelial ion transport will help clarify the involvement of S LC4A 11 in the pathophysiology of CHED.
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SLC4A11 depletion impairs NRF2 mediated antioxidant signaling and increases reactive oxygen species in human corneal endothelial cells during oxidative stress.
TL;DR: The data suggests a possible role of SLC4A11 in regulating oxidative stress, and might be responsible for both the etiology and treatment of corneal endothelial dystrophy.
Corneal dystrophy-causing SLC4A11 mutants: suitability for folding-correction therapy.
TL;DR: Testing the feasibility of rescuing misfolded SLC4A11 protein to the plasma membrane as a therapeutic approach concluded that therapeutics able to increase cell surface localization of ER‐retained SLC 4A11 mutants hold promise to treat CHED2 and FECD patients.
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TL;DR: The phenotype of mice with targeted disruption of the Trpv6 (Trpv 6 KO) epithelial calcium channel exhibit disordered Ca2+ homeostasis, including defective intestinal Ca2- absorption, decreased BMD, deficient weight gain, and reduced fertility.
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SLC4A11 mutations in Fuchs endothelial corneal dystrophy
Eranga N. Vithana,Patricio E. Morgan,Vedam L. Ramprasad,Donald T.H. Tan,Victor H. K. Yong,Divya Venkataraman,Anandalakshmi Venkatraman,Gary Hin-Fai Yam,Soumittra Nagasamy,Ricky W.K. Law,Rama Rajagopal,Chi P. Pang,Govindsamy Kumaramanickevel,Joseph R. Casey,Tin Aung +14 more
TL;DR: The data suggests that SLC4A11 haploinsufficiency and gradual accumulation of the aberrant misfolded protein may play a role in FECD pathology and that reduced levels of SLC3A11 influence the long-term viability of the neural crest derived corneal endothelial cells.
Classification of Corneal Endothelial Disorders Based on Neural Crest Origin
Charles F. Bahn,Harold F. Falls,Gary A. Varley,Roger F. Meyer,Henry F. Edelhauser,William M. Bourne +5 more
TL;DR: The corneal endothelium is derived from the neural crest and may be considered according to a modification of this scheme to reflect its true embryologic origin.
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