Autosomal Recessive CHED Associated With Novel Compound Heterozygous Mutations in SLC4A11

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NaBC1 (the SLC4A11 gene) belongs to the SLC4 family of sodium-coupled bicarbonate (carbonate) transporter proteins and functions as an electrogenic sodium borate cotransporter. Mutations in SLC4A11 cause either corneal abnormalities (corneal hereditary dystrophy type 2) or a combined auditory and visual impairment (Harboyan syndrome). The role of NaBC1 in sensory systems is poorly understood, given the difficulty of studying patients with NaBC1 mutations. We report our findings in Slc4a11 ؊/؊ mice generated to investigate the role of NaBC1 in sensorineural systems. In wild-type mice, specific NaBC1 immunoreactivity was detected in fibrocytes of the spiral ligament, from the basal to the apical portion of the cochlea. NaBC1 immunoreactivity was present in the vestibular labyrinth, in stromal cells underneath the non-immunoreactive sensory epithelia of the macula utricle, sacule, and crista ampullaris, and the membranous vestibular labyrinth was collapsed. Both auditory brain response and vestibular evoked potential waveforms were significantly abnormal in Slc4a11 ؊/؊ mice. In the cornea, NaBC1 was highly expressed in the endothelial cell layer with less staining in epithelial cells. However, unlike humans, the corneal phenotype was mild with a normal slit lamp evaluation. Corneal endothelial cells were morphologically normal; however, both the absolute height of the corneal basal epithelial cells and the relative basal epithelial cell/total corneal thickness were significantly increased in Slc4a11 ؊/؊ mice. Our results demonstrate for the first time the importance of NaBC1 in the audio-vestibular system and provide support for the hypothesis that SLC4A11 should be considered a potential candidate gene in patients with isolated sensorineural vestibular hearing abnormalities.The SLC4 transporter family consists of proteins that mediate bicarbonate (carbonate) transport and include Cl-HCO 3 exchangers, Na/HCO 3 cotransporters, and sodium-driven Cl-HCO 3 exchangers (1). A single member of the family encoded by the SLC4A11 gene does not transport bicarbonate (carbonate) (2, 3). On the basis of sequence homology with other members of the SLC4 family, the protein encoded by SLC4A11 was initially called BTR1 (bicarbonate transporter 1) (2). Subsequently, motivated by its homology with the borate transporter BOR1 in Arabidopsis (4), experiments by Park et al. (3) reported that the transporter functioned in the presence of borate as an electrogenic sodium-borate cotransporter and was renamed NaBC1.Mutations in the SLC4A11 gene are responsible for corneal hereditary dystrophy type 2 (CHED2) 4 and Harboyan syndrome (5-14). In addition to corneal dystrophy, patients with Harboyan syndrome have perceptive hearing loss and nystagmus (7,14). Whether all patients with CHED2 have undiagnosed hearing abnormalities is currently unknown. Heterozygous single nucleotide polymorphisms for SLC4A11 have also been identified in Chinese and Indian patients with Fuchs dystrophy, the most common dystrophic cause of endothelial failure in the...

Section: Discussionmentioning

confidence: 88%

Section: Examples Of Typical Vsep Waveforms In Slc4a11mentioning

confidence: 99%

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Slc4a11 Gene Disruption in Mice

López

Rosenblatt

Kim

et al. 2009

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“…Polymorphisms in the electrogenic sodium bicarbonate cotransporter NBCe2 (SLC4A5) are associated with hypertension (16). Finally, mutations in NaBC1, the electrogenic sodium borate cotransporter encoded by SLC4A11, cause CHED2 disease, Harboyan syndrome, and Fuchs endothelial corneal dystrophy (17)(18)(19)(20).…”

Section: T442cmentioning

confidence: 99%

Oligomeric Structure and Minimal Functional Unit of the Electrogenic Sodium Bicarbonate Cotransporter NBCe1-A

Kao

Sassani

Azimov

et al. 2008

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The electrogenic sodium bicarbonate cotransporter NBCe1-A mediates the basolateral absorption of sodium and bicarbonate in the proximal tubule. In this study the oligomeric state and minimal functional unit of NBCe1-A were investigated. Wildtype (wt) NBCe1-A isolated from mouse kidney or heterologously expressed in HEK293 cells was predominantly in a dimeric state as was shown using fluorescence energy transfer, pulldown, immunoprecipitation, cross-linking experiments, and nondenaturing perfluorooctanoate-PAGE. NBCe1-A monomers were found to be covalently linked by S-S bonds. When each of the 15 native cysteine residues were individually removed on a wt-NBCe1-A backbone, dimerization of the cotransporter was not affected. In experiments involving multiple native cysteine residue removal, both Cys 630 and Cys 642 in extracellular loop 3 were shown to mediate S-S bond formation between NBCe1-A monomers. When native NBCe1-A cysteine residues were individually reintroduced into a cysteineless NBCe1-A mutant backbone, the finding that a Cys 992 construct that lacked S-S bonds functioned normally indicated that stable covalent linkage of NBCe1-A monomers was not a necessary requirement for functional activity of the cotransporter. Studies using concatameric constructs of wt-NBCe1-A, whose activity is resistant to methanesulfonate reagents, and an NBCe1-A T442C mutant, whose activity is completely inhibited by methanesulfonate reagents, confirmed that NBCe1-A monomers are functional. Our results demonstrate that wt-NBCe1-A is predominantly a homodimer, dependent on S-S bond formation that is composed of functionally active monomers.

“…Later, it was shown that SLC4A11 mediates the flux of Na ϩ and OH Ϫ into cells, although SLC4A11 can also mediate Na ϩ /borate cotransport in the presence of borate (6). Mutations in SLC4A11 are associated with autosomal recessive corneal endothelial dystrophy (CHED2) (7,8) and are also found in the Harboyen syndrome (9), a congenital corneal endothelial dystrophy associated with progressive perceptive deafness (10). It has been speculated that endothelial dystrophy and hearing loss result from improper proliferation during fetal development caused by borate-dependent effects on cell proliferation mediated via a mitogen-activated protein kinase (MAPK) pathway or by fluid imbalance in the inner ear (7).…”

mentioning

confidence: 99%

SLC4A11 Prevents Osmotic Imbalance Leading to Corneal Endothelial Dystrophy, Deafness, and Polyuria

Gröger

Fröhlich

Maier

et al. 2010

Maintenance of ion concentration gradients is essential for the function of many organs, including the kidney, the cornea, and the inner ear. Ion concentrations and fluid content in the cornea are regulated by endothelial cells that separate the collagenous avascular corneal stroma from the anterior eye chamber. Failure to maintain correct ion concentrations leads to swelling and destruction of the cornea. In the inner ear, the stria vascularis is responsible for generating proper ion concentrations in the endolymph, which is essential for hearing. Mutations of SLC4A11 in humans lead to syndromes associated with corneal dystrophy and perceptive deafness. The molecular mechanisms underlying these symptoms are poorly understood, impeding therapeutic interventions. The ion transporter SLC4A11 mediates sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions in vitro. Here, we show that SLC4A11 is expressed in the endothelial cells of the cornea where it prevents severe morphological changes of the cornea caused by increased sodium chloride concentrations in the stroma. In the inner ear, SLC4A11 is located in fibrocytes underlying the stria vascularis. Loss of SLC4A11 leads to morphological changes in the fibrocytes and deafness. We demonstrate that SLC4A11 is essential for the generation of the endocochlear potential but not for regulation of potassium concentrations in the endolymph. In the kidney, SLC4A11 is expressed in the thin descending limb of Henle loop. SLC4A11 is essential for urinary concentration, suggesting that SLC4A11 participates in the countercurrent multiplication that concentrates urine in the kidney medulla.