Slc4a11 gene disruption in mice: Cellular targets of sensorineuronal abnormalities

Division of Head and Neck, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2009; 284(39):26882-96. DOI: 10.1074/jbc.M109.008102
Source: PubMed


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.

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    • "Two slc4a11 knockout mice have been described. The first was generated by a retroviral gene trap vector integrated upstream of exon 2 of slc4a11 containing a stop codon (Lopez et al., 2009). The second was generated using a targeting vector causing fusion of exon 10 to beta-galactosidase and deletion of exons 11–18 which leads to truncation of the gene before the first predicted trans-membrane domain (Groger et al., 2010). "
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    ABSTRACT: The choroid plexus epithelium (CPE) is located in the ventricular system of the brain, where it secretes the majority of the cerebrospinal fluid (CSF) that fills the ventricular system and surrounds the central nervous system. The CPE is a highly vascularized single layer of cuboidal cells with an unsurpassed transepithelial water and solute transport rate. Several members of the slc4a family of bicarbonate transporters are expressed in the CPE. In the basolateral membrane the electroneutral Na(+) dependent Cl(-)/HCO3 (-) exchanger, NCBE (slc4a10) is expressed. In the luminal membrane, the electrogenic Na(+):HCO3 (-) cotransporter, NBCe2 (slc4a5) is expressed. The electroneutral Na(+):HCO3 (-) cotransporter, NBCn1 (slc4a7), has been located in both membranes. In addition to the bicarbonate transporters, the Na(+)/H(+) exchanger, NHE1 (slc9a1), is located in the luminal membrane of the CPE. Genetically modified mice targeting slc4a2, slc4a5, slc4a7, slc4a10, and slc9a1 have been generated. Deletion of slc4a5, 7 or 10, or slc9a1 has numerous impacts on CP function and structure in these mice. Removal of the transporters affects brain ventricle size (slc4a5 and slc4a10) and intracellular pH regulation (slc4a7 and slc4a10). In some instances, removal of the proteins from the CPE (slc4a5, 7, and 10) causes changes in abundance and localization of non-target transporters known to be involved in pH regulation and CSF secretion. The focus of this review is to combine the insights gathered from these knockout mice to highlight the impact of slc4 gene deletion on the CSF production and intracellular pH regulation resulting from the deletion of slc4a5, 7 and 10, and slc9a1. Furthermore, the review contains a comparison of the described human mutations of these genes to the findings in the knockout studies. Finally, the future perspective of utilizing these proteins as potential targets for the treatment of CSF disorders will be discussed.
    Frontiers in Physiology 10/2013; 4:304. DOI:10.3389/fphys.2013.00304 · 3.53 Impact Factor
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    • "More recently, hearing defects have been found in individuals with FECD (13). Disruption of murine SLC4A11 gene recapitulates these human phenotypes (12,14), underscoring the conserved role of SLC4A11 in corneal and inner ear function. "
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    ABSTRACT: Three genetic corneal dystrophies congenital hereditary endothelial dystrophy type 2 (CHED2), Harboyan syndrome and Fuchs endothelial corneal dystrophy) arise from mutations of the SLC4a11 gene, which cause blindness from fluid accumulation in the corneal stroma. Selective transmembrane water conductance controls cell size, renal fluid reabsorption and cell division. All known water-channeling proteins belong to the major intrinsic protein family, exemplified by aquaporins (AQPs). Here we identified SLC4A11, a member of the solute carrier family 4 of bicarbonate transporters, as an unexpected addition to known transmembrane water movement facilitators. The rate of osmotic-gradient driven cell-swelling was monitored in X. laevis oocytes and HEK293 cells, expressing human AQP1, NIP5;1 (a water channel protein from plant), hCNT3 (a human nucleoside transporter) and human SLC4A11. hCNT3-expressing cells swelled no faster than control cells, whereas SLC4A11-mediated water permeation at a rate about half that of some AQP proteins. SLC4A11-mediated water movement was: i) similar to some aquaporins in rate, ii) uncoupled from solute-flux, iii) inhibited by stilbene disulfonates (classical SLC4 inhibitors), iv) inactivated in one CHED2 mutant (R125H). Localization of AQP1 and SLC4A11 in human and murine corneal (apical and basolateral, respectively) suggests a cooperative role in mediating trans-endothelial water reabsorption. Slc4a11(-/-) mice manifest corneal edema and distorted endothelial cells, consistent with loss of a water-flux. Observed water-flux through SLC4A11 extends the repertoire of known water movement pathways and call for a re-examination of explanations for water movement in human tissues.
    Human Molecular Genetics 06/2013; 22(22). DOI:10.1093/hmg/ddt307 · 6.39 Impact Factor
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    • "It has been reported that a member of the human SLC4A anion exchanger family, SLC4A1, is used for boron membrane transportation. SLC4A1 has been cloned on the basis of the sequence homology with the plant boron transporter BOR1 (Romero et al., 2004; Lopez et al., 2009). Until now, no information about the relationship between the boron membrane transportation mechanism and SLCA1-3 anion exchangers in humans has been available. "
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    ABSTRACT: Boron is an important micronutrient in plants and animals. The role of boron in living systems includes coordinated regulation of gene expression, growth and proliferation of higher plants and animals. There are several well-defined genes associated with boron transportation and tolerance in plants and these genes show close homology with human anion exchanger genes. Mutation of these genes also characterizes some genetic disorders. We investigated the toxic effects of boric acid on HEK293 cells and mRNA expression of anion exchanger (SLC4A1, SLC4A2 and SLC4A3) genes. Cytotoxicity of boric acid at different concentrations was tested by using the methylthiazolyldiphenyl-tetrazolium bromide assay. Gene expression profiles were examined using quantitative real-time PCR. In the HEK293 cells, the nontoxic upper concentration of boric acid was 250 μM; more than 500 μM caused cytotoxicity. The 250 μM boric acid concentration increased gene expression level of SLC4A2 up to 8.6-fold and SLC4A3 up to 2.6-fold, after 36-h incubation. There was no significant effect of boric acid on SLC4A1 mRNA expression levels.
    Genetics and molecular research: GMR 01/2012; 11(2):847-54. DOI:10.4238/2012.April.3.6 · 0.78 Impact Factor
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