Congenital hereditary endothelial dystrophy (CHED) causes impaired vision resulting from opacification of the cornea. The recessive form of CHED (CHED2) as well as some types of Fuch's endothelial dystrophy and Harboyan syndrome were recently shown to be associated with mutations in the SLC4A11 gene that encodes BTR1/NaBC1, a member of the bicarbonate transporter family. The function and subcellular location of this protein in cornea are unknown, and there is currently no adequate animal model for the study of CHED caused by SLC4A11 mutations. The goals of the proposed experiments are to determine the molecular function of SLC4A11 and its localization in the cornea, and to generate a mouse model for CHED2. The available functional information suggests that SLC4A11 transports Na+ and borate [B(OH)4- ], although no boron transport experiments with this protein have been performed.
Specific Aim 1 A is to use HEK293 cells and a corneal endothelial cell line, with mass-spectrometry, to determine whether mammalian (mouse, human) SLC4A11 cotransports Na+ and boron.
Specific Aim 1 B is to use Xenopus oocytes, with ion-selective microelectrodes, to determine whether SLC4A11 cotransports Na+ and HCO3-.
In Specific Aim 2 we will perform immunohistochemistry to determine whether Slc4a11 is located in the basolateral or apical membrane of the mouse corneal endothelium.
In Specific Aim 3 we will generate and evaluate the phenotype of a mouse model of CHED2 prepared by introducing, to mouse Slc4a11, a point mutation (in the position of human R755Q) that is known to cause CHED2 in humans.

Public Health Relevance

Maintenance of transparency of the cornea is essential for good vision. A variety of conditions can cause the cornea to become cloudy, including an inherited condition known as congenital hereditary endothelial dystrophy (CHED). Some forms of CHED are a result of mutations in a transport protein known as SLC4A11, the function of which has not been well established. The goals of this project are to determine the function of SLC4A11 and to establish a mouse model of CHED.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EY021646-02
Application #
8389867
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2011-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$179,425
Indirect Cost
$35,061
Name
University of Arkansas for Medical Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
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Lee, Seong-Ki; Boron, Walter F; Parker, Mark D (2013) Monitoring ion activities in and around cells using ion-selective liquid-membrane microelectrodes. Sensors (Basel) 13:984-1003
Parker, Mark D; Boron, Walter F (2013) The divergence, actions, roles, and relatives of sodium-coupled bicarbonate transporters. Physiol Rev 93:803-959
Romero, Michael F; Chen, An-Ping; Parker, Mark D et al. (2013) The SLC4 family of bicarbonate (HCOýýýýýý) transporters. Mol Aspects Med 34:159-82