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: 4.6). 08/2009; 284(39):26882-96. DOI: 10.1074/jbc.M109.008102
Source: PubMed

ABSTRACT 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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    ABSTRACT: The SLC4A11 gene mutations cause a variety of genetic corneal diseases including CHED2, Harboyan syndrome, some cases of Fuchs' endothelial dystrophy (FECD) and possibly familial keratoconus. Three N-terminal variants of the human SLC4A11 gene, named SLC4A11-A,-B, and -C are known. The SLC4A11-B variant has been the focus of previous studies. Both the expression of the SLC4A11-C variant in the cornea and its functional properties have not been characterized, and therefore its potential pathophysiologic role in corneal diseases remains to be been explored. In the present study, we demonstrate that SLC4A11-C is the predominant SLC4A11 variant expressed in human corneal endothelial mRNA, and that the transporter functions as an electrogenic H+(OH-) permeation pathway. Disulfonic stilbenes including DIDS, H2DIDS, and SITS, and that are known to bind covalently increased SLC4A11-C mediated H(+)(OH(-)) flux by 150-200% without having a significant effect in mock-transfected cells. Noncovalently interacting DADS was without effect. We tested the efficacy of DIDS on the functionally impaired R109H mutant (SLC4A11-C numbering) that causes CHED2. DIDS (1 mM) increased H(+)(OH(-)) flux through the mutant transporter by ~ 40-90%. These studies provide a basis for future testing of more specific chemically modified dilsulfonic stilbenes as potential therapeutic agents to improve the functional impairment of specific SLC4A11 mutant transporters.
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