Abstract
Late-onset Fuchs endothelial corneal dystrophy (FECD) shows genetic heterogeneity. Identification of SLC4A11 as a candidate gene for congenital hereditary endothelial dystrophy with similar corneal endothelial defects as FECD and reduced mRNA expression of SLC4A11 in the endothelium of FECD cases suggested that this gene may also be involved in pathogenesis of FECD. Mutations in SLC4A11 give rise to SLC4A11 protein marked by retention in the endoplasmic reticulum as a result of mis-folding. We screened 45 sporadic late-onset, 4 early-onset FECD patients and an early-onset autosomal dominant FECD family. We identified three previously unreported missense mutations: c.719G>C (p.W240S), c.1519G>A (p.V507I) and c.1304C>T (p.T434I) in unrelated individuals. These SLC4A11 mutants, expressed in HEK293 cells, had defects in either their cell surface expression or functional activity (rate of osmotically driven water flux). SLC4A11 mutations contribute to 11% (5/45) of sporadic late-onset FECD in the cohort studied. COL8A2, which causes some cases of early-onset FECD, was also screened in this cohort. No mutations were identified in COL8A2, in neither the late-onset cohort nor the early-onset family, suggesting genetic heterogeneity in this FECD family.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Sundin, O. H., Jun, A. S., Broman, K. W., Liu, S. H., Sheehan, S. E., Vito, E. C. et al. Linkage of late-onset Fuchs corneal dystrophy to a novel locus at 13pTel-13q12.13. Invest. Ophthalmol. Vis. Sci. 47, 140–145 (2006).
Gottsch, J. D., Sundin, O. H., Liu, S. H., Jun, A. S., Broman, K. W., Stark, W. J. et al. Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of fuchs corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 46, 1934–1939 (2005).
Biswas, S., Munier, F. L., Yardley, J., Hart-Holden, N., Perveen, R., Cousin, P. et al. Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum. Mol. Genet. 10, 2415–2423 (2001).
Mok, J. W., Kim, H. S. & Joo, C. K. Q455V mutation in COL8A2 is associated with Fuchs' corneal dystrophy in Korean patients. Eye (Lond) 23, 895–903 (2009).
Li, J. Y., Terry, M. A., Goshe, J., Davis-Boozer, D. & Shamie, N. Three-year visual acuity outcomes after Descemet's stripping automated endothelial keratoplasty. Ophthalmology 119, 1126–1129 (2012).
Sundin, O. H., Broman, K. W., Chang, H. H., Vito, E. C., Stark, W. J. & Gottsch, J. D. A common locus for late-onset Fuchs corneal dystrophy maps to 18q21.2-q21.32. Invest. Ophthalmol. Vis. Sci. 47, 3919–3926 (2006).
Riazuddin, S. A., Zaghloul, N. A., Al-Saif, A., Davey, L., Diplas, B. H., Meadows, D. N. et al. Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am. J. Hum. Genet. 86, 45–53 (2010).
Riazuddin, S. A., Eghrari, A. O., Al-Saif, A., Davey, L., Meadows, D. N., Katsanis, N. et al. Linkage of a mild late-onset phenotype of Fuchs corneal dystrophy to a novel locus at 5q33.1-q35.2. Invest. Ophthalmol. Vis. Sci. 50, 5667–5671 (2009).
Afshari, N. A., Li, Y. J., Pericak-Vance, M. A., Gregory, S. & Klintworth, G. K. Genome-wide linkage scan in fuchs endothelial corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 50, 1093–1097 (2009).
Riazuddin, S. A., Parker, D. S., McGlumphy, E. J., Oh, E. C., Iliff, B. W., Schmedt, T. et al. Mutations in LOXHD1, a recessive-deafness locus, cause dominant late-onset Fuchs corneal dystrophy. Am. J. Hum. Genet. 90, 533–539 (2012).
Vithana, E. N., Morgan, P., Sundaresan, P., Ebenezer, N. D., Tan, D. T., Mohamed, M. D. et al. Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2). Nat. Genet. 38, 755–757 (2006).
Vithana, E. N., Morgan, P. E., Ramprasad, V., Tan, D. T., Yong, V. H., Venkataraman, D. et al. SLC4A11 mutations in Fuchs endothelial corneal dystrophy. Hum. Mol. Genet. 17, 656–666 (2008).
Riazuddin, S. A., Vithana, E. N., Seet, L. F., Liu, Y., Al-Saif, A., Koh, L. W. et al. Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophy. Hum. Mutat. 31, 1261–1268 (2010).
Baratz, K. H., Tosakulwong, N., Ryu, E., Brown, W. L., Branham, K., Chen, W. et al. E2-2 protein and Fuchs's corneal dystrophy. New Engl. J. Med. 363, 1016–1024 (2010).
Li, Y. J., Minear, M. A., Rimmler, J., Zhao, B., Balajonda, E., Hauser, M. A. et al. Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy. PLoS ONE 6, e18044 (2011).
Riazuddin, S. A., McGlumphy, E. J., Yeo, W. S., Wang, J., Katsanis, N. & Gottsch, J. D. Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus. Invest. Ophthalmol. Vis. Sci. 52, 2825–2829 (2011).
Thalamuthu, A., Khor, C. C., Venkataraman, D., Koh, L. W., Tan, D. T., Aung, T. et al. Association of TCF4 gene polymorphisms with Fuchs' corneal dystrophy in the Chinese. Invest. Ophthalmol. Vis. Sci. 52, 5573–5578 (2011).
Wieben, E. D., Aleff, R. A., Tosakulwong, N., Butz, M. L., Highsmith, W. E., Edwards, A. O. et al. A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy. PLoS ONE 7, e49083 (2012).
Saumya Pal, S., Raman, R., Ganesan, S., Sahu, C. & Sharma, T. Sankara Nethralaya diabetic retinopathy epidemiology and molecular genetic study (SN–DREAMS III): study design and research methodology. BMC Ophthalmol. 11, 7 (2011).
George, R., Arvind, H., Baskaran, M., Ramesh, S. V., Raju, P. & Vijaya, L. The Chennai glaucoma study: prevalence and risk factors for glaucoma in cataract operated eyes in urban Chennai. Indian J. Ophthalmol. 58, 243–245 (2010).
Kumar, P., Henikoff, S. & Ng, P. C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073–1081 (2009).
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).
Vilas, G. L., Morgan, P. E., Loganathan, S. K., Quon, A. & Casey, J. R. A biochemical framework for SLC4A11, the plasma membrane protein defective in corneal dystrophies. Biochemistry 50, 2157–2169 (2011).
Ruetz, S., Lindsey, A. E. & Kopito, R. R. Function and biosynthesis of erythroid and nonerythroid anion exchangers. Soc. Gen. Physiol. Ser. 48, 193–200 (1993).
Vilas, G. L., Loganathan, S. K., Quon, A., Sundaresan, P., Vithana, E. N. & Casey, J. Oligomerization of SLC4A11 protein and the severity of FECD and CHED2 corneal dystrophies caused by SLC4A11 mutations. Hum. Mutat. 33, 419–428 (2012).
Vilas, G. L., Loganathan, S. K., Liu, J., Riau, A. K., Young, J. D., Mehta, J. S. et al. Transmembrane water flux through SLC4A11: a route defective in genetic corneal diseases. Hum. Mol. Genet. 22, 4579–4590 (2013).
Hemadevi, B., Srinivasan, M., Arunkumar, J., Prajna, N. V. & Sundaresan, P. Genetic analysis of patients with Fuchs endothelial corneal dystrophy in India. BMC Ophthalmol 10, 3 (2010).
Minear, M. A., Li, Y. J., Rimmler, J., Balajonda, E., Watson, S., Allingham, R. R. et al. Genetic screen of African Americans with Fuchs endothelial corneal dystrophy. Mol. Vis. 19, 2508–2516 (2013).
Park, M., Li, Q., Shcheynikov, N., Zeng, W. & Muallem, S. NaBC1 is a ubiquitous electrogenic Na+ -coupled borate transporter essential for cellular boron homeostasis and cell growth and proliferation. Mol. Cell 16, 331–341 (2004).
Jalimarada, S. S., Ogando, D. G., Vithana, E. N. & Bonanno, J. A. Ion transport function of SLC4A11 in corneal endothelium. Invest. Ophthalmol. Vis. Sci. 54, 4330–4340 (2013).
Ramprasad, V. L., Ebenezer, N. D., Aung, T., Rajagopal, R., Yong, V. H., Tuft, S. J. et al. Novel SLC4A11 mutations in patients with recessive congenital hereditary endothelial dystrophy (CHED2). Mutation in brief #958. Online. Hum. Mutat. 28, 522–523 (2007).
Aldave, A. J., Yellore, V. S., Bourla, N., Momi, R. S., Khan, M. A., Salem, A. K. et al. Autosomal recessive CHED associated with novel compound heterozygous mutations in SLC4A11. Cornea 26, 896–900 (2007).
Kumar, A., Bhattacharjee, S., Prakash, D. R. & Sadanand, C. S. Genetic analysis of two Indian families affected with congenital hereditary endothelial dystrophy: two novel mutations in SLC4A11. Mol. Vis. 13, 39–46 (2007).
Desir, J., Moya, G., Reish, O., Van Regemorter, N., Deconinck, H., David, K. L. et al. Borate transporter SLC4A11 mutations cause both Harboyan syndrome and non-syndromic corneal endothelial dystrophy. J. Med. Genet. 44, 322–326 (2007).
Hemadevi, B., Veitia, R. A., Srinivasan, M., Arunkumar, J., Prajna, N. V., Lesaffre, C. et al. Identification of mutations in the SLC4A11 gene in patients with recessive congenital hereditary endothelial dystrophy. Arch. Ophthalmol 126, 700–708 (2008).
Shah, S. S., Al-Rajhi, A., Brandt, J. D., Mannis, M. J., Roos, B., Sheffield, V. C. et al. Mutation in the SLC4A11 gene associated with autosomal recessive congenital hereditary endothelial dystrophy in a large Saudi family. Ophthalmic Genet. 29, 41–45 (2008).
Aldahmesh, M. A., Khan, A. O., Meyer, B. F. & Alkuraya, F. S. Mutational spectrum of SLC4A11 in autosomal recessive CHED in Saudi Arabia. Invest. Ophthalmol. Vis. Sci 50, 4142–4145 (2009).
Paliwal, P., Sharma, A., Tandon, R., Sharma, N., Titiyal, J. S., Sen, S. et al. Congenital hereditary endothelial dystrophy - mutation analysis of SLC4A11 and genotype-phenotype correlation in a North Indian patient cohort. Mol. Vis. 16, 2955–2963 (2010).
Mehta, J. S., Hemadevi, B., Vithana, E. N., Arunkumar, J., Srinivasan, M., Prajna, V. et al. Absence of phenotype-genotype correlation of patients expressing mutations in the SLC4A11 gene. Cornea 29, 302–306 (2010).
Kodaganur, S. G., Kapoor, S., Veerappa, A. M., Tontanahal, S. J., Sarda, A., Yathish, S. et al. Mutation analysis of the SLC4A11 gene in Indian families with congenital hereditary endothelial dystrophy 2 and a review of the literature. Mol. Vis. 19, 1694–1706 (2013).
Park, S. H., Jeong, H. J., Kim, M. & Kim, M. S. A novel nonsense mutation of the SLC4A11 gene in a Korean patient with autosomal recessive congenital hereditary endothelial dystrophy. Cornea 32, e181–e182 (2013).
Kim, J. H., Ko, J. M. & Tchah, H. Fuchs endothelial corneal dystrophy in a heterozygous carrier of congenital hereditary endothelial dystrophy type 2 with a novel mutation in SLC4A11. Ophthalmic. Genet. (e-pub ahead of print 6 February 2014).
Kobayashi, A., Fujiki, K., Murakami, A., Kato, T., Chen, L. Z., Onoe, H. et al. Analysis of COL8A2 gene mutation in Japanese patients with Fuchs' endothelial dystrophy and posterior polymorphous dystrophy. Jpn J. Ophthalmol. 48, 195–198 (2004).
Aldave, A. J., Rayner, S. A., Salem, A. K., Yoo, G. L., Kim, B. T., Saeedian, M. et al. No pathogenic mutations identified in the COL8A1 and COL8A2 genes in familial Fuchs corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 47, 3787–3790 (2006).
Acknowledgements
The work in SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation was part of the project funded by Indian Council of Medical Research, Government of India (no. 53/11/2006-BMS). We thank all the patients for participating in the study. We also thank late Dr G Sitalakshmi (cornea consultant) for her contribution in patient evaluation. Work in the laboratory of JRC was supported by an operating grant from the Canadian Institutes of Health Research. SKL is supported by a graduate studentship from the International Research Training Group in Membrane Biology, supported by Canada’s Natural Sciences and Engineering Research Council.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
Soumittra, N., Loganathan, S., Madhavan, D. et al. Biosynthetic and functional defects in newly identified SLC4A11 mutants and absence of COL8A2 mutations in Fuchs endothelial corneal dystrophy. J Hum Genet 59, 444–453 (2014). https://doi.org/10.1038/jhg.2014.55
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2014.55
This article is cited by
-
Genetic mutations and molecular mechanisms of Fuchs endothelial corneal dystrophy
Eye and Vision (2021)
-
Human Corneal Expression of SLC4A11, a Gene Mutated in Endothelial Corneal Dystrophies
Scientific Reports (2019)
-
The Molecular Basis of Fuchs’ Endothelial Corneal Dystrophy
Molecular Diagnosis & Therapy (2019)
