Borate transporter SLC4A11 mutations cause both Harboyan syndrome and non-syndromic corneal endothelial dystrophy

Désir, Julie; Moya, Graciela; Reish, Orit; Regemorter, N. Van; Deconinck, Hilde; David, Karen L.; Meire, Françoise; Abramowicz, Marc

doi:10.1136/jmg.2006.046904

Cited by 111 publications

(118 citation statements)

References 21 publications

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“…Our results demonstrate that Slc4a11 Ϫ/Ϫ mice are an important new model system for addressing the underlying pathophysiology of the sensory abnormalities in patients with NaBC1 mutations (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Prior to the current study, there was no information regarding the expression of NaBC1 protein in the inner ear.…”

Section: Discussionmentioning

confidence: 88%

“…Therefore, the corneal phenotype in Slc4A11 Ϫ/Ϫ mice differ significantly from the severe corneal phenotype described in patients with mutations in the SLC4A11 gene (5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Examples Of Typical Vsep Waveforms In Slc4a11mentioning

confidence: 99%

“…Mutations in the SLC4A11 gene are responsible for corneal hereditary dystrophy type 2 (CHED2) 4 and Harboyan syndrome (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In addition to corneal dystrophy, patients with Harboyan syndrome have perceptive hearing loss and nystagmus (7,14).…”

mentioning

confidence: 99%

“…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.…”

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Slc4a11 Gene Disruption in Mice

López

Rosenblatt

Kim

et al. 2009

Journal of Biological Chemistry

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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...

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Section: Discussionmentioning

confidence: 88%

Section: Examples Of Typical Vsep Waveforms In Slc4a11mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Slc4a11 Gene Disruption in Mice

López

Rosenblatt

Kim

et al. 2009

Journal of Biological Chemistry

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“…29,30 In addition to mutations in known genes, linkage studies have identified mutations in chromosomal loci such as in chromosome 5 (FCD3), 31 9 (FCD4), 27 13 (FCD1), 32 18 (FCD 2), 33 and potential linkages at chromosome 1, 7, 15, 17, and X, 20 of which the specific mutated genes have not been identified yet. Some of these mutations have also been identified in other types of endothelial dystrophy; the SLC4A11 mutation has also been identified in congenital hereditary endothelial dystrophy 34,35 and perceptive deafness (Harboyan syndrome), 36 and Figure 1 Wound healing response and regenerative potential of recipient endothelial cells of normal and FECD corneas. Here, ultraviolet (UV) radiation is taken as an example to demonstrate the wound healing response of normal and FECD corneal endothelium to oxidative stress-induced damage and apoptosis.…”

Section: Pathophysiology Of Fecdmentioning

confidence: 99%

What does the future hold for the treatment of Fuchs endothelial dystrophy; will ‘keratoplasty’ still be a valid procedure?

Bruinsma

Tong

Melles

2013

Eye

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Fuchs endothelial corneal dystrophy (FECD) is a well recognized corneal disorder characterized by the presence of collagenous warts extending from Descemet membrane (guttae) and endothelial cellular dysfunction due to cell loss and/or degeneration. Because of the characteristic abnormal cell morphology as seen with specular microscopy as well as the limited regenerative capacity in vivo, the endothelial cells were considered to be 'dystrophic'. Hence, FECD is commonly managed by replacement of the endothelium with donor tissue by means of a penetrating or endothelial keratoplasty. The latter procedure has now been refined to the isolated transplantation of a donor Descemet membrane and its endothelium, referred to as Descemet membrane endothelial keratoplasty (DMEK). Unexpectedly, clinical observation made after DMEK seemed to challenge the current concept of the state of the endothelium in FECD; we actually observed an important role for the 'dystrophic' host endothelium in reendothelialization of the denuded DM, and subsequent corneal clearance. In addition, recent studies regarding the pathophysiology of FECD made us realize that the endothelial cells are not 'dystrophic' per se, but in the course of time may have acquired a dysfunction instead. This paper describes the rationale behind this new concept and based on this, discusses the possibilities for future, less invasive treatment modalities for FECD.

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

Hemadevi

Veitia²,

Srinivasan³

et al. 2008

Arch Ophthalmol

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Objective: To identify Solute Carrier family 4 (sodium borate cotransporter) member 11 (SLC4A11) gene mutations associated with autosomal recessive congenital hereditary endothelial dystrophy (CHED2). Methods: DNA extraction from blood, polymerase chain reaction amplification, and direct sequencing of all the exons of the SLC4A11 gene were performed for 26 affected members of 20 unrelated families with CHED2. Results: Of 10 mutations observed, 6 were novel, 1 of which involves a complete deletion of exon 6, identified for the first time, to our knowledge, in SLC4A11. The mutations cosegregated with the disease phenotype and were absent in 200 ethnically matched control chromosomes analyzed. Conclusions: This study increases the number of SLC4A11 gene mutations and confirms the role of this gene in causing CHED2. Clinical examination did not reveal any considerable variability in disease expressivity in patients carrying SLC4A11 mutations. Extensive linkage analysis may reveal the modifier genes involved in causing CHED2 in the SLC4A11 mutations unidentified in 9 families. Clinical Relevance: In India, there is a high frequency of CHED2, possibly related to consanguineous marriages. Counseling could be provided to explain the drawbacks of consanguineous marriages to assist in reducing this devastating disorder.

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Borate transporter SLC4A11 mutations cause both Harboyan syndrome and non-syndromic corneal endothelial dystrophy

Cited by 111 publications

References 21 publications

Slc4a11 Gene Disruption in Mice

Slc4a11 Gene Disruption in Mice

What does the future hold for the treatment of Fuchs endothelial dystrophy; will ‘keratoplasty’ still be a valid procedure?

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

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