Jiao X, Sultana A, Garg P, et al.. Autosomal recessive corneal endothelial dystrophy (CHED2) is associated with mutations in SLC4A11

L V Prasad Eye Institute, Bhaganagar, Telangana, India
Journal of Medical Genetics (Impact Factor: 6.34). 02/2007; 44(1):64-8. DOI: 10.1136/jmg.2006.044644
Source: PubMed

ABSTRACT

To map and identify the gene for autosomal recessive congenital hereditary endothelial dystrophy (CHED2, OMIM 217700), a disorder characterised by diffuse bilateral corneal clouding that may lead to visual impairment and requiring corneal transplantation.
Members of 16 families with autosomal recessive CHED were genotyped for 13 microsatellite markers at the CHED2 locus on chromosome 20p13-12. Two-point linkage analysis was carried out using the FASTLINK version of the MLINK program. Mutation screening was carried out by amplification of exons and flanking regions by polymerase chain reaction, followed by direct automated sequencing.
Linkage and haplotype analysis placed the disease locus within a 2.2 cM (1.3 Mb) interval flanked by D20S198 and D20S889, including SLC4A11. The maximum LOD score of 11.1 was obtained with D20S117 at theta = 0. Sequencing of SLC4A11 showed homozygotic mutations in affected members from 12 of 16 families.
These results confirm that mutations in the SLC4A11 gene cause autosomal recessive CHED.

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Available from: Chitra Kannabiran
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    • "The density of endothelial cells declines and eventually, posterior corneal dystrophies result in serious deterioration of vision. The SLC4A11 gene (MIM #610206) encodes an 891 amino-acid membrane protein [Vilas et al., 2011], whose mutations cause three posterior corneal dystrophies: recessive congenital hereditary endothelial dystrophy type 2 (CHED2; MIM #217700) [Vithana et al., 2006; Jiao et al., 2007; Ramprasad et al., 2007; Sultana et al., 2007; Hemadevi et al., 2008], recessive Harboyan syndrome (HS; MIM #217400) [Desir and Abramowicz, 2008] (a combination of corneal dystrophy and perceptive deafness), and dominant late-onset Fuchs endothelial corneal dystrophy (FECD; MIM #136800) [Vithana et al., 2006; Desir and Abramowicz, 2008; Vithana et al., 2008]. Hearing deficits also have been observed with an increased frequency in individuals with FECD [Stehouwer et al., 2011]. "

    Full-text · Article · Dec 2014 · Biochemistry and Cell Biology
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    • "The density of endothelial cells declines and eventually, posterior corneal dystrophies result in serious deterioration of vision. The SLC4A11 gene (MIM #610206) encodes an 891 amino-acid membrane protein [Vilas et al., 2011], whose mutations cause three posterior corneal dystrophies: recessive congenital hereditary endothelial dystrophy type 2 (CHED2; MIM #217700) [Vithana et al., 2006; Jiao et al., 2007; Ramprasad et al., 2007; Sultana et al., 2007; Hemadevi et al., 2008], recessive Harboyan syndrome (HS; MIM #217400) [Desir and Abramowicz, 2008] (a combination of corneal dystrophy and perceptive deafness), and dominant late-onset Fuchs endothelial corneal dystrophy (FECD; MIM #136800) [Vithana et al., 2006; Desir and Abramowicz, 2008; Vithana et al., 2008]. Hearing deficits also have been observed with an increased frequency in individuals with FECD [Stehouwer et al., 2011]. "
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    ABSTRACT: SLC4A11 mutations cause some cases of the corneal endothelial dystrophies, congenital hereditary endothelial corneal dystrophy type 2 (CHED2), Harboyan Syndrome (HS) and Fuchs endothelial corneal dystrophy (FECD). SLC4A11 protein was recently identified as facilitating water flux across membranes. SLC4A11 point mutations usually cause SLC4A11 misfolding and retention in the endoplasmic reticulum (ER). We set about to test the feasibility of rescuing misfolded SLC4A11 protein to the plasma membrane as a therapeutic approach. Using a transfected HEK293 cell model, we measured functional activity present in cells expressing SLC4A11 variants in combinations representing the state found in CHED2 carriers, affected CHED2, FECD individuals and unaffected individuals. These cells manifest respectively about 60%, 5%, and 25% of the water flux activity, relative to the unaffected (WT alone). ER-retained CHED2 mutant SLC4A11 protein could be rescued to the plasma membrane, where it conferred 25-30% of WT water flux level. Further, some ER-retained CHED2 mutants expressed at 30 °C supported increased water flux compared to 37 °C cultures. Caspase activation and cell vitality assays revealed that expression of SLC4A11 mutants in HEK293 cells does not induce cell death. We conclude that therapeutics able to increase cell surface localization of ER-retained SLC4A11 mutants hold promise to treat CHED2 and FECD patients. This article is protected by copyright. All rights reserved.
    Full-text · Article · Sep 2014 · Human Mutation
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    • "It prevents morphological abnormalities of the cornea caused by increased sodium chloride concentrations in the stroma. Mutations in SLC4A11 have been known to cause Harboyan Syndrome (congenital corneal endothelial dystrophy with progressive perceptive deafness) [27], Corneal Endothelial Dystrophy Type 2 (bilateral corneal dystrophy characterized by corneal opacification and nystagmus) [28], and Fuchs Endothelial Dystrophy (ocular disorder characterized by focal wart-like guttata that arise from DM and develop in the central cornea, epithelial blisters, reduced vision and pain) [29]. "
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    ABSTRACT: Considerable interest has been generated for the development of suitable corneal endothelial graft alternatives through cell-tissue engineering, which can potentially alleviate the shortage of corneal transplant material. The advent of less invasive suture-less key-hole surgery options such as Descemet's Stripping Endothelial Keratoplasty (DSEK) and Descemet's Membrane Endothelial Keratoplasty (DMEK), which involve transplantation of solely the endothelial layer instead of full thickness cornea, provide further impetus for the development of alternative endothelial grafts for clinical applications. A major challenge for this endeavor is the lack of specific markers for this cell type. To identify genes that reliably mark corneal endothelial cells (CECs) in vivo and in vitro, we performed RNA-sequencing on freshly isolated human CECs (from both young and old donors), CEC cultures, and corneal stroma. Gene expression of these corneal cell types was also compared to that of other human tissue types. Based on high throughput comparative gene expression analysis, we identified a panel of markers that are: i) highly expressed in CECs from both young donors and old donors; ii) expressed in CECs in vivo and in vitro; and iii) not expressed in corneal stroma keratocytes and the activated corneal stroma fibroblasts. These were SLC4A11, COL8A2 and CYYR1. The use of this panel of genes in combination reliably ascertains the identity of the CEC cell type.
    Full-text · Article · Jul 2013 · PLoS ONE
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