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

Abstract

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.

References

  1. 1

    Doyne, R.W. Peculiar condition of choroiditis occurring in several members of the same family. Trans. Ophthalmol. Soc. UK 19, 71 –71 (1899).

  2. 2

    Forni, S. & Babel, J. Étude clinique et histologique de la malattia leventinse: affection appartenant au groupe des dégénérescences hyalines du pôle postérieur. Ophthalmologica 143, 313–322 (1962).

    CAS  Article  Google Scholar 

  3. 3

    Vogt, A. in Handbuch der gesammten Augenheilkunde. Untersuchungsmethoden (eds Graefe, A. & Saemisch, T.) 1–118 (Verlag von Wilhelm Engelman, Berlin, 1925).

    Google Scholar 

  4. 4

    Collins, T. A pathological report upon a case of Doyne's choroiditis ('honey-comb' or 'family choroidits'). Ophthalmoscope 11, 537–538 (1913).

    Google Scholar 

  5. 5

    Heon, E. et al. Linkage of autosomal-dominant radial drusen (malattia leventinese) to chromosome 2p16-21. Arch. Ophthalmol. 114, 193–198 (1996).

    CAS  Article  Google Scholar 

  6. 6

    Gregory, C.Y. et al. The gene responsible for autosomal dominant Doyne's honeycomb retinal dystrophy (DHRD) maps to chromosome 2p16. Hum. Mol. Genet. 5, 1055–1059 ( 1996).

    CAS  Article  Google Scholar 

  7. 7

    Edwards, A.O. et al. Malattia leventinese: refinement of the genetic locus and phenotypic variability in autosomal dominant macular drusen. Am. J. Ophthalmol. 126, 417–424 (1998).

    CAS  Article  Google Scholar 

  8. 8

    Silvestri, G., Johnston, P.B. & Hughes, A.E. Is genetic predisposition an important risk factor in age-related macular degeneration? Eye 8, 564–568 (1994).

    Article  Google Scholar 

  9. 9

    Meyers, S.M. A twin study on age-related macular degeneration. Trans. Am. Ophthalmol. Soc. 92, 775–843 ( 1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Heiba, I.M., Elston, R.C., Klein, B.E. & Klein, R. Sibling correlations and segregation analysis of age-related maculopathy: the Beaver Dam eye study. Genet. Epidemiol. 11, 51–67 (1994).

    CAS  Article  Google Scholar 

  11. 11

    Bressler, N.M., Bressler, S.B. & Fine, S.L. Age-related macular degeneration. Surv. Ophthalmol. 32, 375–413 (1988).

    CAS  Article  Google Scholar 

  12. 12

    Evans, J. & Wormald, R. Is the incidence of registrable age-related macular degeneration increasing? Br. J. Ophthalmol. 80, 9–14 (1996 ).

    CAS  Article  Google Scholar 

  13. 13

    Klein, R., Klein, B.E. & Linton, K.L. Prevalence of age-related maculopathy. The Beaver Dam eye study. Ophthalmology 99, 933– 943 (1992).

    CAS  Article  Google Scholar 

  14. 14

    Vingerling, J.R. et al. The prevalence of age-related maculopathy in the Rotterdam study. Ophthalmology 102, 205– 210 (1995).

    CAS  Article  Google Scholar 

  15. 15

    Sarks, J.P., Sarks, S.H. & Killingsworth, M.C. Evolution of soft drusen in age-related macular degeneration. Eye 8, 269–283 (1994).

    Article  Google Scholar 

  16. 16

    Bird, A.C. et al. An international classification and grading system for age- related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv. Ophthalmol. 39, 367–374 (1995).

    CAS  Article  Google Scholar 

  17. 17

    Jay, M., Plant, C., Evans, K. & Gregory, C.Y. Doyne revisited. Eye 10, 469–472 (1996).

    Article  Google Scholar 

  18. 18

    Tran, H., Mattei, M., Godyna, S. & Argraves, W.S. Human fibulin-1D: molecular cloning, expression and similarity with S1-5 protein, a new member of the fibulin gene family. Matrix Biol. 15, 479–493 (1997).

    CAS  Article  Google Scholar 

  19. 19

    Lecka-Czernik, B., Lumpkin, C.K.J. & Goldstein, S. An overexpressed gene transcript in senescent and quiescent human fibroblasts encoding a novel protein in the epidermal growth factor-like repeat family stimulates DNA synthesis. Mol. Cell. Biol. 15, 120–128 (1995).

    CAS  Article  Google Scholar 

  20. 20

    Dietz, H.C. et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352, 337–339 (1991).

    CAS  Article  Google Scholar 

  21. 21

    Dietz, H.C., Saraiva, J.M., Pyeritz, R.E., Cutting, G.R. & Francomano, C.A. Clustering of fibrillin (FBN1) missense mutations in Marfan syndrome patients at cysteine residues in EGF-like domains. Hum. Mutat. 1, 366– 374 (1992).

    CAS  Article  Google Scholar 

  22. 22

    Wells, J. et al. Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nature Genet. 3, 213–218 ( 1993).

    CAS  Article  Google Scholar 

  23. 23

    Weber, B.H.F., Vogt, G., Pruett, R.C., Stohr, H. & Felbor, U. Mutations in the tissue inhibitor of metalloproteinases-3 (timp3) in patients with sorsbys fundus dystrophy. Nature Genet. 8, 352–356 ( 1994).

    CAS  Article  Google Scholar 

  24. 24

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

    CAS  Article  Google Scholar 

  25. 25

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

    CAS  Article  Google Scholar 

  26. 26

    Marquardt, A. et al. Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease). Hum. Mol. Genet. 7, 1517– 1525 (1998).

    CAS  Article  Google Scholar 

  27. 27

    Buffone, G.J. & Darlington, G.J. Isolation of DNA from biological specimens without extraction with phenol. Clin. Chem. 31, 164–165 (1985).

    CAS  PubMed  Google Scholar 

  28. 28

    Nishimura, D.Y. et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nature Genet. 19, 140–147 (1998).

    CAS  Article  Google Scholar 

  29. 29

    Ikegawa, S., Toda, T., Okui, K. & Nakamura, Y. Structure and chromosomal assignment of the human S1-5 gene (FBNL) that is highly homologous to fibrillin. Genomics 35, 590– 592 (1996).

    CAS  Article  Google Scholar 

  30. 30

    Fingert, J.H. et al. Characterization and comparison of the human and mouse GLC1A glaucoma genes. Genome Res. 8, 377– 384 (1998).

    CAS  Article  Google Scholar 

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Acknowledgements

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 or 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). https://doi.org/10.1038/9722

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