Nature 352, 330 - 334 (25 July 1991); doi:10.1038/352330a0

Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes

Brendan Lee^*, Maurice Godfrey^†, Emilia Vitale^*, Hisae Hori^‡, Marie-Geneviéve Mattei^§, Mansoor Sarfarazi, Petros Tsipouras, Francesco Ramirez^*¶ & David W. Hollister^†£

^*Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, New York 10029, USA
^† Munroe Center for Human Genetics/Meyer Rehabilitation Institute, Departments of Pediatrics and Pathology, University of Nebraska Medical Center, Omaha, Nebraska 68131, USA
^‡ Department of Tissue Physiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101, Japan
^§ Hopital d'Enfants de la Timone (U.242, INSERM), Marseilles 13385, France
Molecular Genetics Laboratory, Department of Pediatrics, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
^¶ To whom correspondence should be addressed
^£ Deceased.

MARFAN syndrome (MFS), one of the most common genetic disorders of connective tissue, is characterized by skeletal, cardiovascular and ocular abnormalities¹. The incidence of the disease is about 1 in 20,000, with life expectancy severely reduced because of cardiovascular complications. As the underlying defect is unknown, MFS diagnosis is based solely on clinical criteria. Certain phenotypic features of MFS are also shared by other conditions, which may be genetically distinct entities although part of a clinical continuum. Immunohistochemical studies have implicated fibrillin, a major component of elastin-associated microfibrils², in MFS aetiology^{3, 4}. Genetic linkage analysis with random probes has independently localized the MFS locus to chromosome 15 (refs 5–7). Here we report that these two experimental approaches converge with the cloning and mapping of the fibrillin gene to chromosome 15ql5–21, and with the establishment of linkage to MFS. We also isolated a second fibrillin gene and mapped it to chromosome 5q23–31. We linked this novel gene to a condition, congenital contractual arachnodactyly, that shares some of the features of MFS¹. Thus, the cosegregation of two related genes with two related syndromes implies that fibrillin mutations are likely to be responsible for different MFS phenotypes.

References

1.	Pyeritz, R. E. in Principle and Practice of Medical Genetics 2nd edn (eds Emery, E. H. & Rimoin, D. L.) 1047−1063 (Churchill Livingstone, New York, 1990).
2.	Inoué, S. & Leblond, C. P. Am. J. Anat. 176, 121−138 (1986). | PubMed |
3.	Hollister, D. W., Godfrey, M., Sakai, L. Y. & Pyeritz, R. E. New Engl. J. Med. 323, 152−159 (1990). | PubMed | ChemPort |
4.	Godfrey, M. et al. Am. J. hum. Genet 46, 652−660 (1990). | PubMed | ChemPort |
5.	Kainulainen, K., Pulkkinen, L., Savolainen, A., Kaitila, I. & Peltonen, L. New Engl. J. Med. 323, 935−939 (1990). | PubMed | ISI | ChemPort |
6.	Dietz, H. C. et al. Genomics 9, 355−361 (1991). | Article | PubMed | ChemPort |
7.	Tsipouras, P., Sarfarazi, M., Devi, A., Weiffenbach, B. & Boxer, M. Proc. natn. Acad. Scl. U.S.A. 88, 4486−4488. | ChemPort |
8.	Sakai, L. Y., Keene, D. R. & Engvall, E. J. Cell Biol. 103, 2499−2509 (1986). | Article | PubMed | ISI | ChemPort |
9.	Maddox, B. K., Sakai, L. Y., Keene, D. R. & Glanville, R. W. J. biol. Chem. 264, 21382−21385 (1989).
10.	Carpenter, G. & Cohen, S. J. biol. Chem. 265, 7709−7712 (1990). | PubMed | ISI | ChemPort |
11.	Walker, B. A., Beighton, P. H. & Murdoch, J. L. Ann. Intern. Med. 71, 349−352 (1969). | PubMed | ChemPort |
12.	Beals, R. K. & Hecht, F. J. Bone Jt Surg. 53, 987−993 (1971). | ChemPort |
13.	Lee, B., Vissing, H., Ramirez, F., Rogers, D. & Rimoin, D. Science 244, 978−980 (1989). | PubMed | ISI | ChemPort |
14.	Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning, A Laboratory Manual 2nd edn (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1989).
15.	Sanger, F., Nicklen, S. & Coulson, A. R. Proc. natn. Acad. Sci. U.S.A. 74, 5463−5467 (1977). | ChemPort |
16.	Mattei, M. G. et al. Hum. Genet. 69, 268−271 (1991).
17.	Lee, B., Vitale, E., Superti-Furga, A., Steinmann, B. & Ramirez, F. J. biol. Chem. 266, 5256−5259 (1991). | PubMed | ISI | ChemPort |
18.	Ott, J. Am. J. hum. Genet. 26, 588−597 (1974). | PubMed | ISI | ChemPort |
19.	Lathrop, G. M., Lalouel, J. M., Junien, C. & Ott, J. Proc. natn. Acad. Sci. U.S.A. 81, 3443−3446 (1984). | ChemPort |