Identification of Mutations in the SLC4A11 Gene in Patients With Recessive Congenital Hereditary Endothelial Dystrophy

Hemadevi, Boomiraj; Veitia, Reiner A.; Srinivasan, Muthiah; Arunkumar, Jambulingam; Prajna, Namperumalsamy Venkatesh; Lesaffre, Corinne; Sundaresan, Periasamy

doi:10.1001/archopht.126.5.700

Cited by 64 publications

(50 citation statements)

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“…Briefly, 1.2 × 10 6 cells were combined in 100 μl of T Buffer (Invitrogen) with 4 μg of cDNA, encoding HA-tagged WT SLC4A11, FECD (E399K) [Vithana et al, 2008], or CHED2 (E143K) [Hemadevi et al, 2008;Ramprasad et al, 2007] mutants, or with 2 μg of the mutant cDNA and the same amount of WT HA-SLC4A11 cDNA. Cells were pulsed three times for 20 ms at 1,400 V and seeded onto semipermeable polycarbonate Transwell filters (Corning, NY), containing DMEM/F12 (1:1) medium supplemented with 20% (v/v) FBS.…”

Section: Ha-slc4a11 Expression In Mdck Cellsmentioning

confidence: 99%

“…HEK 293 cells were transiently transfected with cDNAs encoding HA-tagged WT SLC4A11, FECD (E399K, G709E, T754M) [Vithana et al, 2008], or CHED2 (E143K, C386R, R755W) [Hemadevi et al, 2008;Ramprasad et al, 2007] mutants, or cotransfected with equal amounts of these cDNAs and WT Myc-SLC4A11, as described above. Samples were processed to determine the efficiency of cell surface processing as described previously [Vilas et al, 2011].…”

Section: Cell Surface Processing Assaymentioning

confidence: 99%

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Oligomerization of SLC4A11 protein and the severity of FECD and CHED2 corneal dystrophies caused bySLC4A11mutations

et al. 2011

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Mutations in the SLC4A11 gene, which encodes a plasma membrane borate transporter, cause recessive congenital hereditary endothelial corneal dystrophy type 2 (CHED2), corneal dystrophy and perceptive deafness (Harboyan syndrome), and dominant late-onset Fuchs endothelial corneal dystrophy (FECD). We analyzed missense SLC4A11 mutations identified in FECD and CHED2 patients and expressed in transfected HEK 293 cells. Chemical cross-linking and migration in nondenaturing gels showed that SLC4A11 exists as a dimer. Furthermore, co-immunoprecipitation of epitope-tagged proteins revealed heteromeric interactions between wild-type (WT) and mutant SLC4A11 proteins. When expressed alone, FECD- and CHED2-causing mutant SLC4A11 proteins are primarily retained intracellularly. Co-expression with WT SLC4A11 partially rescued the cell surface trafficking of CHED2 mutants, but not FECD mutants. CHED2 alleles of SLC4A11 did not affect cell surface processing of WT SLC4A11. In contrast, FECD mutants reduced WT cell surface processing efficiency, consistent with dominant inheritance of FECD. The reduction in movement of WT protein to the cell surface caused by FECD SLC4A11 helps to explain the dominant inheritance of this disorder. Similarly, the failure of CHED2 mutant SLC4A11 to affect the processing of WT protein, explains the lack of symptoms found in CHED2 carriers and the recessive inheritance of the disorder.

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Section: Ha-slc4a11 Expression In Mdck Cellsmentioning

confidence: 99%

Section: Cell Surface Processing Assaymentioning

confidence: 99%

Oligomerization of SLC4A11 protein and the severity of FECD and CHED2 corneal dystrophies caused bySLC4A11mutations

et al. 2011

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“…Homozygous mutations in SLC4A11 as a cause of CHED2 and/or Harboyan syndrome in the absence of consanguinity have been reported previously [19,20]. As we were not able to examine other relatives except for the proband's daughter, we cannot exclude the possibility of a larger deletion on the second allele, however, this type of mutation has not been reported for SLC4A11 [21].…”

Section: Discussionmentioning

confidence: 85%

Detailed Assessment of Renal Function in a Proband with Harboyan Syndrome Caused by a Novel Homozygous <b><i>SLC4A11 </i></b>Nonsense Mutation

Lišková

Ďuďáková²,

Tesař³

et al. 2014

Ophthalmic Res

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Background/Aims: To identify the underlying molecular genetic cause of disease in a patient with Harboyan syndrome and to perform a detailed assessment of her renal function. We also assessed the influence of the SLC4A11 mutation identified on the corneal endothelium in the heterozygous state. Methods: A 55-year-old female was examined ophthalmologically, audiologically and nephrologically including 24-hour urine collection. The coding region of SLC4A11 was directly sequenced. Specular microscopy was performed in the proband's 21-year-old daughter. Results: The proband had bilateral iridectomy at the age of 3 months because of an initial diagnosis of congenital glaucoma and since the age of 12 years she underwent several keratoplasties in each eye. Nephrological examination did not reveal any abnormalities. Moderate bilateral sensorineural hearing loss was confirmed by audiometry. A novel homozygous mutation predicted to lead to a premature stop codon at the protein level, c.2188C>T; p.(Arg730*), was identified in SLC4A11. No changes in corneal endothelial cell morphology or density were observed in the heterozygous daughter. Conclusion: In contrast to the Slc4a11^-/- mouse, no abnormalities in daily renal ion excretion or polyuria were observed in the Harboyan syndrome patient. The mutation identified does not affect corneal endothelial cell morphology or density in the heterozygous state. © 2014 S. Karger AG, Basel

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“…The remaining three cell lines express the SLC4A11 disease alleles A269V (CHED), E143K (CHED), and G709E (FECD), 9,12,14 along with a double HA tag after H564. A269V was chosen because culture of this mutant in cells at 308C induced partial rescue to the cell surface.…”

Section: Amplex Red High Throughput Assay Of Cell Surface Slc4a11 Abumentioning

confidence: 99%

High Throughput Assay Identifies Glafenine as a Corrector for the Folding Defect in Corneal Dystrophy–Causing Mutants of SLC4A11

Chiu

Mandziuk

Loganathan

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Chiu AM, Mandziuk JJ, Loganathan SK, Alka K, Casey JR. High throughput assay identifies glafenine as a corrector for the folding defect in corneal dystrophy-causing mutants of SLC4A11. Invest Ophthalmol Vis Sci. 2015;56:7739-7753. DOI:10.1167/ iovs.15-17802 PURPOSE. Protein misfolding, causing retention of nascent protein in the endoplasmic reticulum (ER), is the most common molecular phenotype for disease alleles of membrane proteins. Strategies are needed to identify therapeutics able to correct such folding/trafficking defects. Mutations of SLC4A11, a plasma membrane transport protein of the human corneal endothelial cell layer, cause cases of congenital hereditary endothelial dystrophy, Harboyan syndrome, and Fuchs' endothelial corneal dystrophy. Most SLC4A11 mutations induce SLC4A11 misfolding and retention in the ER.METHODS. An assay amenable to high-throughput screening was developed to quantify SLC4A11 at the plasma membrane, enabling a search for potential traffic-correcting small molecules. The assay was validated by comparing cell surface abundance of SLC4A11 mutants measured in the assay to observations from confocal immunofluorescence and values from cell surface biotinylation. Functionality of mutant proteins was assessed, using a confocal microscopic green fluorescent protein (GFP) water flux assay where relative rates of cell swelling are compared. RESULTS.A small-scale screen revealed that the nonsteroidal anti-inflammatory drugs (NSAIDs), glafenine, ibuprofen, and acetylsalicylic acid dissolved in 0.2% dimethyl sulfoxide (DMSO), partially rescued the trafficking defect in some SLC4A11 mutants, expressed in HEK293 cells. These SLC4A11 mutants retained functional activity when rescued to the plasma membrane by glafenine treatment. Glafenine was effective with an EC 50 of 1.5 6 0.7 lM.CONCLUSIONS. These data suggest that glafenine, and perhaps other NSAIDs, hold potential as therapeutics for misfolded membrane proteins, like SLC4A11. The high throughput approach described here can be modified to identify correctors of other misfolded plasma membrane proteins that cause eye disease.

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Identification of Mutations in the SLC4A11 Gene in Patients With Recessive Congenital Hereditary Endothelial Dystrophy

Cited by 64 publications

References 18 publications

Oligomerization of SLC4A11 protein and the severity of FECD and CHED2 corneal dystrophies caused bySLC4A11mutations

Oligomerization of SLC4A11 protein and the severity of FECD and CHED2 corneal dystrophies caused bySLC4A11mutations

Detailed Assessment of Renal Function in a Proband with Harboyan Syndrome Caused by a Novel Homozygous <b><i>SLC4A11 </i></b>Nonsense Mutation

High Throughput Assay Identifies Glafenine as a Corrector for the Folding Defect in Corneal Dystrophy–Causing Mutants of SLC4A11

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