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

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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 (cf) retina.
Figure 6: Segregation of the 797–801delAACT mutation in families with the STGD3 (ac) and adMD (d) phenotypes.

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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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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) doi:10.1038/83817

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