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: 5.64). 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, Aug 26, 2015
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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.
    Human Mutation 09/2014; 35(9). DOI:10.1002/humu.22601 · 5.05 Impact Factor
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    • "In the present report, we only examined a subset of missense alleles of SLC4A11. In CHED2, a series of SLC4A11 nonsense mutations have been identified [Jiao et al., 2007; Kumar et al., 2007; Sultana et al., 2007]. Since we have not characterized the behavior of these proteins, we can only speculate about how they fit into our explanation of the recessive inheritance of CHED2. "
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    ABSTRACT: Mutations in the SLC4A11 gene, which encodes a plasma membrane borate transporter, cause recessive congenital hereditary endothelial corneal dystrophy type 2 (CHED2), corneal dystrophy and perceptive deafness (Harboyan syndrome), and dominant late-onset Fuchs endothelial corneal dystrophy (FECD). We analyzed missense SLC4A11 mutations identified in FECD and CHED2 patients and expressed in transfected HEK 293 cells. Chemical cross-linking and migration in nondenaturing gels showed that SLC4A11 exists as a dimer. Furthermore, co-immunoprecipitation of epitope-tagged proteins revealed heteromeric interactions between wild-type (WT) and mutant SLC4A11 proteins. When expressed alone, FECD- and CHED2-causing mutant SLC4A11 proteins are primarily retained intracellularly. Co-expression with WT SLC4A11 partially rescued the cell surface trafficking of CHED2 mutants, but not FECD mutants. CHED2 alleles of SLC4A11 did not affect cell surface processing of WT SLC4A11. In contrast, FECD mutants reduced WT cell surface processing efficiency, consistent with dominant inheritance of FECD. The reduction in movement of WT protein to the cell surface caused by FECD SLC4A11 helps to explain the dominant inheritance of this disorder. Similarly, the failure of CHED2 mutant SLC4A11 to affect the processing of WT protein, explains the lack of symptoms found in CHED2 carriers and the recessive inheritance of the disorder.
    Human Mutation 02/2012; 33(2):419-28. DOI:10.1002/humu.21655 · 5.05 Impact Factor
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    • "Mutations of SLC4A11 also cause Harboyan syndrome (corneal dystrophy with perceptive deafness; CDPD) in which CHED is accompanied by sensorineural hearing loss appearing in about the second decade of life (Desir et al. 2007). AR-CHED appears to be genetically homogeneous since the same locus accounts for the disorder in families from different populations with about 67 different mutations identified in the SLC4A11 gene so far indicating the high degree of allelic heterogeneity in CHED2 (Vithana et al. 2006; Aldave et al. 2007a; Desir et al. 2007; Jiao et al. 2007; Kumar et al. 2007; Ramprasad et al. 2007; Sultana et al. 2007; Hemadevi et al. 2008; Shah et al. 2008; Aldahmesh et al. 2009). In contrast to the AR-CHED phenotype arising from SLC4A11 mutations in humans, a mouse knockout for slc4a11 did not show any detectable abnormality in the corneal endothelium of slc4a11 −/− mice; the endothelial cell size, number and morphology were comparable with wild-type mice, as was corneal clarity and thickness (Lopez et al. 2009). "
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    ABSTRACT: The corneal endothelium maintains the level of hydration in the cornea. Dysfunction of the endothelium results in excess accumulation of water in the corneal stroma, leading to swelling of the stroma and loss of transparency. There are four different corneal endothelial dystrophies that are hereditary, progressive, non-inflammatory disorders involving dysfunction of the corneal endothelium. Each of the endothelial dystrophies is genetically heterogeneous with different modes of transmission and/or different genes involved in each subtype. Genes responsible for disease have been identified for only a subset of corneal endothelial dystrophies. Knowledge of genes involved and their function in the corneal endothelium can aid understanding the pathogenesis of the disorder as well as reveal pathways that are important for normal functioning of the endothelium.
    Journal of Genetics 12/2009; 88(4):487-94. DOI:10.1007/s12041-009-0067-1 · 1.01 Impact Factor
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