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A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy

Nature Genetics volume 27, pages 89–93 (2001)Cite this article

Abstract

Stargardt-like macular dystrophy (STGD3, MIM 600110) and autosomal dominant macular dystrophy (adMD) are inherited forms of macular degeneration characterized by decreased visual acuity, macular atrophy and extensive fundus flecks1,2,3. Genetic mapping data suggest that mutations in a single gene may be responsible for both conditions, already known to bear clinical resemblance1,2,3. Here we limit the minimum genetic region for STGD3 and adMD to a 0.6-cM interval by recombination breakpoint mapping and identify a single 5-bp deletion within the protein-coding region of a new retinal photoreceptor-specific gene, ELOVL4, in all affected members of STGD3 and adMD families. Bioinformatic analysis of ELOVL4 revealed that it has homology to a group of yeast proteins that function in the biosynthesis of very long chain fatty acids. Our results are therefore the first to implicate the biosynthesis of fatty acids in the pathogenesis of inherited macular degeneration.

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Figure 1
Figure 2: Physical map of the STGD3/adMD gene region.
Figure 3: Comparison of human ELOVL4 and mouse Elovl4 protein sequences with the product of the yeast ELO3 gene, Elo3p (a), and hydropathy profile analysis of the ELOVL4 and Elo3p proteins (b).
Figure 4: Expression analysis of ELOVL4.
Figure 5: In situ hybridization of ELOVL4 mRNA in rhesus monkey (a,b) and mouse (c–f) retina.
Figure 6: Segregation of the 797–801delAACT mutation in families with the STGD3 (a–c) and adMD (d) phenotypes.

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References

  1. Stone, E.M. et al. Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q. Arch. Ophthalmol. 112, 765–772 (1994).

    Article  CAS  Google Scholar 

  2. Edwards, A.O. et al. Autosomal dominant Stargardt-like macular dystrophy: I. clinical characterization, longitudinal follow-up, and evidence for a common ancestry in families linked to chromosome 6q14. Am. J. Ophthalmol. 127, 426–435 (1999).

    Article  CAS  Google Scholar 

  3. Griesinger, I.B., Sieving, P.A. & Ayyagari, R. Autosomal dominant macular atrophy at 6q14 excludes CORD7 and MCDR1/PBCRA loci. Invest. Ophthalmol. Vis. Sci. 41, 248–255 (2000).

    CAS  PubMed  Google Scholar 

  4. Lagali, P.S. et al. Autosomal dominant Stargardt-like macular dystrophy segregating in a large Canadian family. Can. J. Ophthalmol. 5, 315–324 (2000).

    Article  Google Scholar 

  5. Oh, C.S., Toke, D.A., Mandala, S. & Martin, C.E. ELO2 and ELO3, homologues of the Saccharomyces cerevisiae ELO1 gene, function in fatty acid elongation and are required for sphingolipid formation. J. Biol. Chem. 272, 17376–17384 (1997).

    Article  CAS  Google Scholar 

  6. Tvrdik, P. et al. Cig30, a mouse member of a novel membrane protein gene family, is involved in the recruitment of brown adipose tissue. J. Biol. Chem. 272, 31738–31746 (1997).

    Article  CAS  Google Scholar 

  7. Tvrdik, P. et al. Role of a new mammalian gene family in the biosynthesis of very long chain fatty acids and sphingolipids. J. Cell Biol. 149, 707–318 (2000).

    Article  CAS  Google Scholar 

  8. Shanklin, J., Whittle, E. & Fox, B.G. Eight histidine residues are catalytically essential in a membrane-associated iron enzyme, stearoyl-CoA desaturase, and are conserved in alkane hydroxylase and xylene monooxygenase. Biochemistry 33, 12787–12794 (1994).

    Article  CAS  Google Scholar 

  9. Jackson, M.R., Nilsson, T. & Peterson, P.A. Identification of a consensus motif for retention of transmembrane proteins in the endoplasmic reticulum. EMBO J. 9, 3153–162 (1990).

    Article  CAS  Google Scholar 

  10. Jackson, M.R., Nilsson, T. & Peterson, P.A. Retrieval of transmembrane proteins to the endoplasmic reticulum. J. Cell Biol. 121, 317–333 (1993).

    Article  CAS  Google Scholar 

  11. Schroder, S., Schimmoller, F., Singer-Kruger, B. & Riezman, H. The Golgi-localization of yeast Emp47p depends on its di-lysine motif but is not affected by the ret1-1 mutation in α-COP. J. Cell Biol. 131, 895–912 (1995).

    Article  CAS  Google Scholar 

  12. Cinti, D.L., Cook, L., Nagi, M.N. & Suneja, S.K. The fatty acid chain elongation system of mammalian endoplasmic reticulum. Prog. Lipid Res. 31, 1–51 (1992).

    Article  CAS  Google Scholar 

  13. Allikmets, R.L. et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nature Genet. 15, 236–246 (1997).

    Article  CAS  Google Scholar 

  14. Sun, H. & Nathans, J. Stargardt's ABCR is localized to the disc membrane of retinal rod outer segments. Nature Genet. 17, 15–16 (1997).

    Article  Google Scholar 

  15. Illing, M., Molday, L.L. & Molday, R.S. The 220-kDa rim protein of retinal rod outer segments is a member of the ABC transporter superfamily. J. Biol. Chem. 11, 10303–10310 (1997).

    Article  Google Scholar 

  16. Molday, L.L., Rabin, A.R. & Molday, R.S. ABCR expression in foveal cone photoreceptors and its role in Stargardt macular dystrophy. Nature Genet. 25, 257–258 (2000).

    Article  CAS  Google Scholar 

  17. Allikmets, R. et al. Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies. Hum. Genet. 104, 449–453 (1999).

    Article  CAS  Google Scholar 

  18. Fliesler, S.J. & Anderson, R.E. Chemistry and metabolism of lipids in the vertebrate retina. Prog. Lipid Res. 22, 79–131 (1983).

    Article  CAS  Google Scholar 

  19. Sprecher, H., Luthria, D.L. Mohammed, B.S. & Baykousheva, S.P. Reevaluation of the pathways for the biosynthesis of polyunsaturated fatty acids. J. Lipid Res. 36, 2471–2477 (1995).

    CAS  PubMed  Google Scholar 

  20. Luthria, D.L., Mohammed, B.S. & Sprecher, H. Regulation of the biosynthesis of 4,7,10,13,16,19-docosahexaenoic acid. J. Biol. Chem. 271, 16020–16025 (1996).

    Article  CAS  Google Scholar 

  21. Weng, J. et al. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell 98, 13–23 (1999).

    Article  CAS  Google Scholar 

  22. Sun, H., Molday, R.S. & Nathans, J. Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease. J. Biol. Chem. 274, 8269–8281 (1999).

    Article  CAS  Google Scholar 

  23. Ahn, J., Wong, J.T. & Molday, R.S. The effect of lipid environment and retinoids on the ATPase activity of ABCR, the photoreceptor ABC transporter responsible for Stargardt macular dystrophy. J. Biol. Chem. 275, 20399–20405 (2000).

    Article  CAS  Google Scholar 

  24. Petrukhin, K. et al. Identification of the gene responsible for Best macular dystrophy. Nature Genet. 19, 241–247 (1998).

    Article  CAS  Google Scholar 

  25. Stone, E.M. et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nature Genet. 22, 199–202 (1999).

    Article  CAS  Google Scholar 

  26. Weber, B.H., Vogt, G., Pruett, R.C., Stohr, H. & Felbor, U. Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nature Genet. 8, 352–356 (1994).

    Article  CAS  Google Scholar 

  27. Zhang, K., Bither, P.P., Park, R., Donoso, L.A., Seidman, J.G. & Seidman, C.E. A dominant Stargardt's macular dystrophy locus maps to chromosome 13q34. Arch. Ophthalmol. 112, 759–764 (1994).

    Article  CAS  Google Scholar 

  28. Shah, A.B. et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am. J. Hum. Genet. 61, 317–328 (1997).

    Article  CAS  Google Scholar 

  29. Austin, C.P., Feldman, D., Ida, J. & Cepko, C.L. Vertebrate retinal ganglion cells are selected from competent progenitors by the action of Notch. Development 121, 3637–3650 (1995).

    CAS  PubMed  Google Scholar 

  30. Kyte, J. & Doolittle, R.F. A simple method for displaying the hydropathic character of a protein. J. Mol. Biol. 157, 105–132 (1982).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the members of the sequencing group (Merck Research Labs) for shotgun cloning and sequencing; C.T. Caskey for support and advice; A. Marmorstein and J. Hollyfield for helpful discussions; M. Rayborn for critical reading of the manuscript; J. Seidman, C. Seidman and P. Bither for advice and help in the early phase of this work; Y. Shugart for help with linkage analysis; and patients with STGD3 and adMD and members of their families for participation. Supported by NIH EY00401 and Grant Ritter Fund (K.Z.), Helen Keller Eye Research Foundation (Y.L.), Foundation Fighting Blindness, Hunt Valley, Maryland (D.J.Z., P.A.S., R.A.), E.A. Baker Foundation, AHFMR, and Foundation Fighting Blindness, Canada (P.W.W.), and Howard Hughes Medical Institute, of which M.H. is an assistant investigator. This research was supported in part by funding provided to Johns Hopkins University under a Research Collaboration Agreement between Johns Hopkins University and Merck & Co., Inc.

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Author notes

  1. Kang Zhang

    Present address: Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA

Authors and Affiliations

  1. Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Kang Zhang, Zhengya Yu, Zhenglin Yang, Yang Li & Donald J. Zack

  2. Department of Molecular Biology & Genetics, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Donald J. Zack

  3. Department of Molecular, Cellular and Developmental Biology, Howard Hughes Medical Institute, University of Colorado at Boulder, Boulder, Colorado, USA

    Marina Kniazeva & Min Han

  4. Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA

    Wen Li, David J. Figueroa, Christopher P. Austin, Robert J. Gould & Konstantin Petrukhin

  5. Department of Human Genetics, Merck Research Laboratories, West Point, Pennsylvania, USA

    Michael L. Metzker

  6. Departments of Ophthalmology and Pathology, Columbia University, New York, New York, USA

    Rando Allikmets

  7. W.K. Kellog Eye Center, University of Michigan, Ann Arbor, Michigan, USA

    Laura E. Kakuk, Paul A. Sieving & Radha Ayyagari

  8. Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada

    Pamela S. Lagali & Paul W. Wong

  9. Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada

    Paul W. Wong & Ian M. MacDonald

  10. Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada

    Paul W. Wong & Ian M. MacDonald

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Correspondence to Konstantin Petrukhin.

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Zhang, K., Kniazeva, M., Han, M. et al. A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet 27, 89–93 (2001). https://doi.org/10.1038/83817

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