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A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy


Malattia Leventinese (ML) and Doyne honeycomb retinal dystrophy (DHRD) refer to two autosomal dominant diseases characterized by yellow-white deposits known as drusen that accumulate beneath the retinal pigment epithelium1,2,3,4 (RPE). Both loci were mapped to chromosome 2p16-21 (Refs 5,6) and this genetic interval has been subsequently narrowed6,7. The importance of these diseases is due in large part to their close phenotypic similarity to age-related macular degeneration (AMD), a disorder with a strong genetic component8,10 that accounts for approximately 50% of registered blindness in the Western world11,12,13,14. Just as in ML and DHRD, the early hallmark of AMD is the presence of drusen15,16. Here we use a combination of positional and candidate gene methods to identify a single non-conservative mutation (Arg345Trp) in the gene EFEMP1 (for EGF-containing fibrillin-like extracellular matrix protein 1) in all families studied. This change was not present in 477 control individuals or in 494 patients with age-related macular degeneration. Identification of this mutation may aid in the development of an animal model for drusen, as well as in the identification of other genes involved in human macular degeneration.

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Figure 1: Fundus photograph of a patient affected with ML.
Figure 2: BACs and YACs comprising the minimum tiling path are shown.
Figure 3: Representative chromatograms generated by fluorescent dye-terminator sequencing of PCR products from affected individuals reveal a C→T transition at the first nucleotide of codon 345, which would be expected to alter the amino acid at this position from an arginine to a tryptophan.
Figure 4: EFEMP1 expression analysis a, Northern-blot analysis of mouse EFEMP1 expression.


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We thank S. Sneed, T. Polk, J.D.M. Gass, J. Slakter, L. Yannuzzi, D. Keenum, A. Franceschetti, S. Forni, C. Anastasi-Forni, S. Sarks, C.A. Harper, P. Allen, R. Buttery, C. McCarty, G. Morgan, S. Kirmani and S. Bhattacharya for sharing patients or DNA samples; L. Streb, R. Hockey, H. Haines, L. Affatigato, G. Beck, C. Taylor, S. Krob, G. Metthez, F. Ahmad, V. Buchillier, V. Kaltenrieder, R. McNeil and M. Cain for technical assistance; and C. Fasser for support of retinal degeneration research. Supported in part by NIH grants EY10539 and EY11515, the Carver Charitable Trust, The Ruth and Milton Steinbach Foundation, The Grousbeck Family Foundation, The Foundation Fighting Blindness, the Swiss National Science Foundation grant 32-053750.98, the Fondation Telethon Action Suisse, The Royal Victorian Institute for the Blind and an unrestricted grant from Research to Prevent Blindness.

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Correspondence to Edwin M. Stone, Francis L. Munier or Val C. Sheffield.

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

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