Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mapping a gene for congenital fibrosis of the extraocular muscles to the centromeric region of chromosome 12


Congenital Fibrosis of the Extraocular Muscles (CFEOM) is an autosomal dominant, ocular disorder characterized by congenital, nonprogressive, bilateral ptosis and external ophthalmoplegia. The pathophysiology of this disorder is unknown and it is unclear if it has a primary neurogenic or myopathic etiology. We report linkage of this disorder, in two unrelated families, to markers in the pericentromeric region of human chromosome 12. D12S59 does not recombine with the disease giving a two–point lod score of 12.5 (θ = 0.00). D12S87 and D12S85 flank the CFEOM locus with two–point lod scores of 8.9 (θ = 0.03) and 5.4 (θ = 0.03) respectively, defining a region of 8 cM. These data establish a map location for CFEOM and demonstrate that this may be a genetically homogeneous disorder.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Ringel, S.P., Wilson, W.B., Barden, M.T. & Kaiser, K.K. Histochemistry of human extraocular muscle. Arch. Ophthalmol. 96, 1067–1072 (1978).

    CAS  Article  Google Scholar 

  2. 2

    Oda, K. Motor innervation and acetylcholine receptor distribution of human extraocular muscle fibres. J. neurol. Sci. 74, 125–133 (1986).

    CAS  Article  Google Scholar 

  3. 3

    Kaminski, H.J., al Hakim, M., Leigh, R.J., Katirji, M.B. & Ruff, R.L. Extraocular muscles are spared in advanced Duchenne dystrophy. Ann. Neurol. 32, 586–588 (1992).

    CAS  Article  Google Scholar 

  4. 4

    Prendergast, R.A. et al. Relative sparing of extraocular muscles in Duchenne muscular dystrophy. Invest. ophth. vis. Sci. (Supp) 34, 1120 (1993).

    Google Scholar 

  5. 5

    Kosmorsky, G. & Johns, D.R. Neuro–ophthalmologic manifestations of mitochondrial DNA disorders: chronic progressive external ophthalmoplegia, Keams-Sayre syndrome, and Leber's hereditary optic neuropathy. Neurol. Clin. 9, 147–161 (1991).

    CAS  Article  Google Scholar 

  6. 6

    Rowland, L.P. Progressive external opthalmoplegia and ocular myopathies. in Handbook of Clinical Neurology: Myopathies (eds Rowland, L.P. & DiMauro, S.) 287–329 (Elsevier Science Publishers B.V., Amsterdam, 1992).

    Google Scholar 

  7. 7

    Harley, R.D., Rodrigues, M.M. & Crawford, J.S. Congenital fibrosis of the extraocular muscles. J. pediatr. ophthalmol. Strabismus 15, 346–358 (1978).

    CAS  PubMed  Google Scholar 

  8. 8

    Hiatt, R.L. & Halle, A.A. General fibrosis syndrome. Ann. Ophthalmol. 15, 1103–1109 (1983).

    CAS  PubMed  Google Scholar 

  9. 9

    Hansen, E. Congenital general fibrosis of the extraocular muscles. Acta. Ophthalmol. (Copenh) 46, 469–476 (1968).

    CAS  Article  Google Scholar 

  10. 10

    Brodsky, M.C., Pollock, S.C. & Buckley, E.G. Neural misdirection in congenital ocular fibrosis syndrome: implications and pathogenesis. J. pediat. ophthalmol. Strabismus 26, 159–161 (1989).

    CAS  PubMed  Google Scholar 

  11. 11

    Lawford, J.B. Congenital hereditary defect of ocular movements. Trans. ophthalmol. Soc. U.K. 8, 262–274 (1888).

    Google Scholar 

  12. 12

    Houtman, W.A., van Weeden, T.W., Robinson, P.H., deVires, B. & Hoogenraad, T.U. Hereditary congenital external ophthalmoplegia. Ophthalmologica 193, 207–218 (1986).

    CAS  Article  Google Scholar 

  13. 13

    Rumph, M. Fibrose du muscle droit Inferieur, anomalies d'insertions et aplasies musculaires, une cause rare de troubles hereditaires non progressifs et congenltaux de la motilite oculaire. Ann. Oculistique 207, 831–829 (1974).

    Google Scholar 

  14. 14

    Crawford, J.S. Congenital fibrosis syndrome. Can. J. Ophthalmol. 5, 331–336 (1970).

    CAS  PubMed  Google Scholar 

  15. 15

    Laughlin, R.C. Congenital fibrosis of the extraocular muscles; a report of six cases. Amer. J. Ophthalmology 41, 432–438 (1956).

    CAS  Article  Google Scholar 

  16. 16

    Brown, H.W. in Strabismus Ophthalmic Symposium (ed. Allen, J.H.) 205–236 (C.V. Mosby, St. Louis, 1950).

    Google Scholar 

  17. 17

    Appleton, R.E., Chitayat, D., Jan, J.E., Kennedy, R. & Hall, J.G. Joubert's syndrome associated with congenital ocular fibrosis and histidinemia. Arch. Neurol. 46, 579–582 (1989).

    CAS  Article  Google Scholar 

  18. 18

    Kalpakian, B., Bateman, B.J., Sparkes, R.S. & Wood, G.K. Congenital ocular fibrosis syndrome associated with the Prader-Willi syndrome. J. pediat. ophthalmol. Strabismus 23, 170–173 (1986).

    CAS  PubMed  Google Scholar 

  19. 19

    Nemet, P., Godel, V., Ron, S. & Lazar, M. Ocular congenital fibrosis syndrome. Metab. pediatr. syst. Ophthalmol. 8, 172–174 (1985).

    CAS  Google Scholar 

  20. 20

    Mutirangura, A., Ledbetter, S.A., Kuwano, A., Chinault, A.C. & Ledbetter, D.H. Dinucleotide repeat polymorphism at the GABAA receptor beta 3 (GABRB3) locus In the Angelman/Prader-Willi region (AS/PWS) of chromosome 15. Hum. molec. Genet. 1, 67 (1992).

    CAS  Article  Google Scholar 

  21. 21

    NIH/CEPH Collaborative Mapping Group. A comprehensive genetic linkage map of the human genome. Science 258, 67–86 (1992).

  22. 22

    Weissenbach, J. et al. A second-generation linkage map of the human genome. Nature 359, 794–801 (1992).

    CAS  Article  Google Scholar 

  23. 23

    Holt, M. et al. An index linkage map for human chromosome 12. Am. J. hum. Genet. 53, A1016 (1993).

    Google Scholar 

  24. 24

    Matise, T.C., Perlin, M. & Chakravarti, A. Automated construction of genetic linkage maps using an expert system (MultiMap): a human genome linkage map. Nature Genet. 6, 384–390 (1994).

    CAS  Article  Google Scholar 

  25. 25

    Craig, I., Gemmill, R. & Kucherlapati, R. Report of the first international workshop on human chromosome 12 mapping. Cytogenet. Cell Genet. 61, 243–251 (1992).

    CAS  Article  Google Scholar 

  26. 26

    Jones, C. & Moore, E.E. Localization of a gene which complements branched-chain amino acid transaminase deficiency to the short arm of human chromosome 12. Hum. Genet. 66, 206–211 (1984).

    CAS  Article  Google Scholar 

  27. 27

    Adams, M.D., Kerlavage, A.R., Fields, C. & Venter, J.C. 3,400 new expressed sequence tags identify diversity of transcripts in human brain. Nature Genet. 4, 256–266 (1993).

    CAS  Article  Google Scholar 

  28. 28

    Cannizzaro, L.A. et al. Human homeo box-containing genes located at chromosome regions 2q31–2q37 and 12q12–12q13. Am. J. hum. Genet. 41, 1–15 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Villaseca, A. Strabismus fixus. Am. J. Ophthalmol. 48, 751–762 (1959).

    CAS  Article  Google Scholar 

  30. 30

    Khodadoust, A.A. & von Noorden, G.K. Bilateral Vertical Retraction Syndrome: A Family Study. Arch. Ophthalmol. 78, 606–612 (1967).

    CAS  Article  Google Scholar 

  31. 31

    Leone, C.R. & Weinstein, G.W. Orbital fibrosis wlth enophthalmos. Ophthalmic Surg. 3, 71–75 (1972).

    Google Scholar 

  32. 32

    Kunkel, L.M. et al. Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc. natn. Acad. Sci. U.S.A. 74, 1245–1249 (1977).

    CAS  Article  Google Scholar 

  33. 33

    Wu, S., Seino, S. & Bell, G.I. Human collagen, type II, alpha 1, (COL2A1)gene: VNTR polymorphism detected by gene amplification. Nucl. Acids Res. 18, 3102 (1990).

    CAS  Article  Google Scholar 

  34. 34

    Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. natn. Acad. Sci. U.S.A. 81, 3443–3446 (1984).

    CAS  Article  Google Scholar 

  35. 35

    Conneally, P.M. et al. Report of the committee on methods of linkage analysis and reporting. Cytogenet. Cell Genet. 40, 356–359 (1985).

    CAS  Article  Google Scholar 

  36. 36

    Ott, J. Analysis of Human Genetic Linkage Rev. edn. (Johns Hopkins University Press, Baltimore, 1991).

    Google Scholar 

Download references

Author information



Rights and permissions

Reprints and Permissions

About this article

Cite this article

Engle, E., Kunkel, L., Specht, L. et al. Mapping a gene for congenital fibrosis of the extraocular muscles to the centromeric region of chromosome 12. Nat Genet 7, 69–73 (1994).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing