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Identification of the gene responsible for Best macular dystrophy

Abstract

Best macular dystrophy (BMD), also known as vitelliform macular dystrophy (VMD2; OMIM 153700), is an autosomal dominant form of macular degeneration characterized by an abnormal accumulation of lipofuscin within and beneath the retinal pigment epithelium cells. In pursuit of the disease gene, we limited the minimum genetic region by recombination breakpoint analysis and mapped to this region a novel retina-specific gene (VMD2). Genetic mapping data, identification of five independent disease-specific mutations and expression studies provide evidence that mutations within the candidate gene are a cause of BMD. The 3′ UTR of the candidate gene contains a region of antisense complementarity to the 3′ UTR of the ferritin heavy-chain gene ( FTH1), indicating the possibility of antisense interaction between VMD2 and FTH1 transcripts.

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Figure 1: Physical map of the BMD region.
Figure 2: Conceptual translation of the VMD2 mRNA.
Figure 3: The G383→C mutation associated with BMD in S1.
Figure 4: Evolutionary conservation of five mutation regions.
Figure 5: Segregation of the T783A mutation in Dutch family Nx1.
Figure 6: Expression analysis of VMD2.
Figure 7: In situ hybridization of VMD2 mRNA in mouse retina.

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Acknowledgements

The authors thank the members of the sequencing group (Merck Research Labs) for shot-gun cloning and sequencing; J. F. Hess, Y. Liu, W. Bailey, S. Lutsenko and D. Underwood for their advice and helpful discussions; T. Stout for a generous gift of human retina and helpful comments. Special thanks are extended to S. Socher for arranging and coordinating the international collaboration. The authors greatly appreciate the previous work of C. Graff and A. Eriksson on collection of clinical samples and genetic mapping. We would like to thank patients with BMD and members of their families for participation in this study. The study was supported by grants from the Swedish Medical Research Council (09747, 12717), the Synfrämjandets Research Foundation, the Crown Princess Margareta Foundation for the Visually Impaired and the Margit Thyselius Foundation. C.W. was supported as research associate by the Swedish Medical Research Council.

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Correspondence to Konstantin Petrukhin or Claes Wadelius.

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Petrukhin, K., Koisti, M., Bakall, B. et al. Identification of the gene responsible for Best macular dystrophy. Nat Genet 19, 241–247 (1998). https://doi.org/10.1038/915

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