Congenital Hereditary Endothelial Dystrophy Caused by SLC4A11 Mutations Progresses to Harboyan Syndrome

Siddiqui, Salina; Zenteno, Juan Carlos; Rice, Anthony J.; Chacón‐Camacho, Oscar F.; Naylor, Steven; Parra, David Rivera-De la; Spokes, David; James, N. T.; Toomes, Carmel; Inglehearn, Chris F.; Ali, Manir

doi:10.1097/ico.0000000000000041

Cited by 50 publications

(29 citation statements)

References 27 publications

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“…7 Harboyan syndrome (HS), which presents as with CHED, but with addition of sensorineuronal deafness, is an alternate manifestation of CHED that is also caused by SLC4A11 mutations. 8,9 SLC4A11 mutations may cause some cases of Fuchs' endothelial corneal dystrophy (FECD), 10 a dominantly inherited disease affecting 4% lifetime incidence of people over age 40, as quantified by the presence of guttae (hallmark bumps on Descemet's membrane). 11 When studied in model cells, the most common molecular phenotype of mutant membrane proteins is mild misfolding.…”

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confidence: 99%

Ophthalmic Nonsteroidal Anti-Inflammatory Drugs as a Therapy for Corneal Dystrophies Caused by SLC4A11 Mutation

Kumari

Casey

2018

Invest. Ophthalmol. Vis. Sci.

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Citation: Alka K, Casey JR. Ophthalmic nonsteroidal anti-inflammatory drugs as a therapy for corneal dystrophies caused by SLC4A11 mutation. Invest Ophthalmol Vis Sci. 2018;59:4258-4267. https://doi.org/ 10.1167/iovs.18-24301 PURPOSE. SLC4A11 is a plasma membrane protein of corneal endothelial cells. Some mutations of the SLC4A11 gene result in SLC4A11 protein misfolding and failure to mature to the plasma membrane. This gives rise to some cases of Fuchs' endothelial corneal dystrophy (FECD) and congenital hereditary endothelial dystrophy (CHED). We screened ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) for their ability to correct SLC4A11 folding defects.METHODS. Five ophthalmic NSAIDs were tested for their therapeutic potential in some genetic corneal dystrophy patients. HEK293 cells expressing CHED and FECD-causing SLC4A11 mutants were grown on 96-well dishes in the absence or presence of NSAIDs. Ability of NSAIDs to correct mutant SLC4A11 cell-surface trafficking was assessed with a bioluminescence resonance energy transfer (BRET) assay and by confocal microscopy. The ability of mutant SLC4A11-expressing cells to mediate water flux (SLC4A11 mediates water flux across the corneal endothelial cell basolateral membrane as part of the endothelial water pump) was measured upon treatment with ophthalmic NSAIDs.RESULTS. BRET-assays revealed significant rescue of SLC4A11 mutants to the cell surface by 4 of 5 NSAIDs tested. The NSAIDs, diclofenac and nepafenac, were effective in moving endoplasmic reticulum-retained missense mutant SLC4A11 to the cell surface, as measured by confocal immunofluorescence. Among intracellular-retained SLC4A11 mutants, 20 of 30 had significant restoration of cell surface abundance upon treatment with diclofenac. Diclofenac restored mutant SLC4A11 water flux activity to the level of wild-type SLC4A11 in some cases.CONCLUSIONS. These results encourage testing diclofenac eye drops as a treatment for corneal dystrophy in patients whose disease is caused by some SLC4A11 missense mutations.

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confidence: 99%

Ophthalmic Nonsteroidal Anti-Inflammatory Drugs as a Therapy for Corneal Dystrophies Caused by SLC4A11 Mutation

Kumari

Casey

2018

Invest. Ophthalmol. Vis. Sci.

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“…This raises the question as to whether CHED2 is unrecognized CDPD and several studies recommend monitoring CHED2 patients for progressive hearing loss. 5,10,11 The Leu843Pro mutation was previously reported as one of two distinct mutations detected in two non-consanguineous CDPD families of South American Indian and Dutch background. 5 The finding of this mutation in an Irish pedigree means that this is the most ethnically diverse mutation reported to date; the majority of reports have been from Indian and middle eastern populations.…”

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confidence: 98%

Homozygous SLC4A11 mutation in a large Irish CHED2 pedigree

Hand

McGuire

Parfrey

et al. 2016

Ophthalmic Genetics

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“…SLC4A11 is predominantly expressed in the kidney, salivary glands, testis, thyroid glands, trachea (Parker et al ), pancreas, liver, and spleen (Park et al ), as well as the cornea (Damkier et al ). Mutations in SLC4A11 are considered responsible for human corneal disorders, such as autosomal recessive congenital hereditary endothelial dystrophy (CHED2) (Jiao et al ; Hand et al ), Harboyan syndrome (Desir and Abramowicz ; Liskova et al ; Siddiqui et al ) and Fuchs endothelial corneal dystrophy (Vithana et al ; Kim et al ). Similarly, Slc4a11 disruption in mice caused corneal endothelial dystrophy (Gröger et al ; Han et al ) and sensorineural abnormalities (Lopez et al ).…”

Section: Introductionmentioning

confidence: 99%

Slc4a11disruption causes duct cell loss and impairs NaCl reabsorption in female mouse submandibular glands

et al. 2019

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Slc4a11, a member of the Slc4 HCO3 − transporter family, has a wide tissue distribution. In mouse salivary glands, the expression of Slc4a11 mRNA was more than eightfold greater than the other nine members of the Slc4 gene family. The Slc4a11 protein displayed a diffuse subcellular distribution in both the acinar and duct cells of mouse submandibular glands (SMG). Slc4a11 disruption induced a significant increase in the Na+ and Cl− concentrations of stimulated SMG saliva, whereas it did not affect the fluid secretion rate in response to either β‐adrenergic or cholinergic receptor stimulation. Heterologous expressed mouse Slc4a11 acted as a H+/OH− transporter that was uncoupled of Na+ or Cl− movement, and this activity was blocked by ethyl‐isopropyl amiloride (EIPA) but not 4,4′‐Diisothiocyanato‐2,2′‐stilbenedisulfonic acid (DIDS). Slc4a11 disruption revealed that Slc4a11 does not play a major role in intracellular pH regulation in mouse salivary gland cells. In contrast, NaCl reabsorption was impaired in the SMG saliva of female compared to male Slc4a11 null mice, which correlated with the loss of duct cells and a decrease in expression of the duct‐cell‐specific transcription factor Ascl3. Together, our results suggest that Slc4a11 expression regulates the number of ducts cells in the mouse SMG and consequently NaCl reabsorption.

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Congenital Hereditary Endothelial Dystrophy Caused by SLC4A11 Mutations Progresses to Harboyan Syndrome

Abstract: Supplemental Digital Content is Available in the Text.

Cited by 50 publications

References 27 publications

Ophthalmic Nonsteroidal Anti-Inflammatory Drugs as a Therapy for Corneal Dystrophies Caused by SLC4A11 Mutation

Ophthalmic Nonsteroidal Anti-Inflammatory Drugs as a Therapy for Corneal Dystrophies Caused by SLC4A11 Mutation

Homozygous SLC4A11 mutation in a large Irish CHED2 pedigree

Slc4a11disruption causes duct cell loss and impairs NaCl reabsorption in female mouse submandibular glands

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