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  • Title: Molecular phenotype of SLC4A11 missense mutants: Setting the stage for personalized medicine in corneal dystrophies.
    Author: Alka K, Casey JR.
    Journal: Hum Mutat; 2018 May; 39(5):676-690. PubMed ID: 29327391.
    Abstract:
    SLC4A11 mutations cause cases of congenital hereditary endothelial dystrophy (CHED), Harboyan syndrome (HS), and Fuchs endothelial corneal dystrophy (FECD). Defective water reabsorption from corneal stroma by corneal endothelial cells (CECs) leads to these corneal dystrophies. SLC4A11, in the CEC basolateral membrane, facilitates transmembrane movement of H2 O, NH3 , and H+ -equivalents. Some SLC4A11 disease mutants have impaired folding, leading to a failure to move to the cell surface, which in some cases can be corrected by the drug, glafenine. To identify SLC4A11 mutants that are targets for folding-correction therapy, we examined 54 SLC4A11 missense mutants. Cell-surface trafficking was assessed on immunoblots, by the level of mature, high molecular weight, cell surface-associated form, and using a bioluminescence resonance energy transfer assay. Low level of cell surface trafficking was found in four out of 18 (20%) of FECD mutants, 19/ out of 31 (61%) of CHED mutants, and three out of five (60%) of HS mutants. Amongst ER-retained mutants, 16 showed increased plasma membrane trafficking when grown at 30°C, suggesting that their defect has potential for rescue. CHED-causing point mutations mostly resulted in folding defects, whereas the majority of FECD missense mutations did not affect trafficking, implying functional impairment. We identified mutations that make patients candidates for folding correction of their corneal dystrophy.
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