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Mammalian Genome

, Volume 5, Issue 11, pp 696–700 | Cite as

Of mice and Marfan: genetic linkage analyses of the fibrillin genes, Fbn1 and Fbn2, in the mouse genome

  • C. Goldstein
  • P. Liaw
  • S. A. Jimenez
  • A. M. Buchberg
  • L. D. Siracusa
Original Contributions

Abstract

The fibrillin genes, FBN1 and FBN2, encode large extracellular matrix glycoproteins involved in the structure and function of microfibrils. Mutations in FBN1 are found in patients with Marfan syndrome, a heritable connective tissue disease that primarily affects the cardiovascular, ocular, and skeletal systems. We extended the studies of these genes by determining their chromosomal position in the mouse genome. Restriction fragment length polymorphisms (RFLPs) between the progenitors of an interspecific backcross involving AEJ/Gn and Mus spretus mice were used to establish the segregation patterns of the murine homologs, Fbn1 and Fbn2, in the backcross progeny. The results position Fbn1 between the B2m and Illa genes on mouse Chromosome (Chr) 2 and establish its candidacy for the Tight skin (Tsk) mutation. The results position Fbn2 between the D18Mit35 and Pdgfrb loci in the central region of mouse Chr 18. Fbn2 maps near three mutations [bouncy (bc), plucked (pk), and shaker with syndactyly (sy)] and may be a candidate for the pk mutation.

Keywords

Restriction Fragment Length Polymorphism Connective Tissue Disease Mouse Genome Marfan Syndrome Segregation Pattern 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Abraham, J.A., Whang, J.L., Tumolo, A., Mergia, A., Friedman, J., Gospodarowicz, D., Fiddes, J.C. (1986). Human basic fibroblast growth factor; nucleotide sequence and genomic organization. J. Embryol. 5, 2523–2528.Google Scholar
  2. Corson, G.M., Chalberg, S.C., Dietz, H.C., Charbonneau, N.L., Sakai, L.Y. (1993). Fibrillin binds calcium and is coded by cDNAs that reveal a multidomain structure and alternatively spliced exons at the 5′ end. Genomics 17, 476–484.Google Scholar
  3. Davisson, M.T., Johnson, K.R. (1993). Mouse Chromosome 18. Mamm. Genome 4 (Suppl.) S253-S260.Google Scholar
  4. Dietrich, W., Miller, J., Katz, H., Joyce, D., Steen, R., Lincoln, S., Daly, M., Reeve, M.P., Weaver, A., Anagnostopoulos, P., Goodman, N., Dracopoli, N., Lander, E.S. (1993). SSLP genetic map of the mouse (Mus musculus). In Genetic Maps: Locus Maps of Complex Genomes, Book 4: Nonhuman Vertebrates, S.J. O'Brien, ed. (Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press), pp. 4,110–4,142.Google Scholar
  5. Dietz, H.C., Cutting, G.R., Pyeritz, R.E., Maslen, C.L., Sakai, L.Y., Corson, G.M., Puffenberger, E.G., Hamosh, A., Nanthakumar, E.J., Curristin, S.M., Stetten, G., Meyers, D.A., Francomano, C.A. (1991). Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352, 337–339.Google Scholar
  6. Dietz, H.C., Pyeritz, R.E., Puffenberger, E.G., Kendzior, R.J., Corson, G.M., Maslen, C.L., Sakai, L.Y., Francomano, C.A., Cutting, G.R. (1992). Marfan phenotype variability in a family segregating a missense mutation in the epidermal growth factor-like motif of the fibrillin gene. J. Clin. Invest. 89, 1674–1680.Google Scholar
  7. Dietz, H.C., McIntosh, I., Sakai, L.Y., Corson, G.M., Chalberg, S.C., Pyeritz, R.E., Francomano, C.A. (1993). Four novel FBN 1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome. Genomics 17, 468–475.Google Scholar
  8. Doel, M.S. (1963). The development of the inner ear in mice homozygous for shaker-with-syndactylism. J. Embryol. Exp. Morph. 11, 493–512.Google Scholar
  9. Everett, E.T., Pablos, J.L., Harris, S.E., LeRoy, E.C., Norris, J.S. (1994). The tight-skin (Tsk) mutation is closely linked to B2m on mouse Chromosome 2. Mamm. Genome 5, 55–57.Google Scholar
  10. Gardi, C., Martorana, P.A., de Santi, M.M., van Even, P., Lungarella, G. (1989). A biochemical and morphological investigation of the early development of genetic emphysema in Tight-skin mice. Exp. Mol. Pathol. 50, 398–410.Google Scholar
  11. Godfrey, M. (1993). The Marfan Syndrome. In Heritable disorders of connective tissue, 5th ed. V.A. McKusick, ed. (St. Louis, MO.: Mosby), pp. 51–135.Google Scholar
  12. Green, E.L. (1981). Breeding systems. In The Mouse in Biomedical Research, Vol. I, H.L. Foster, J.D. Small, J.G. Fox, eds. (New York: Academic Press), pp. 91–104.Google Scholar
  13. Green, M.C. (1989). Catalog of mutant genes and polymorphic loci. In Genetic Variants and Strains of the Laboratory Mouse, M.F. Lyon, A.G. Searle, eds. (Oxford: Oxford University Press), pp. 12–403.Google Scholar
  14. Green, M.C., Sweet, H.O., Bunker, L.E. (1976). Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton. Am. J. Pathol. 82, 493–507.Google Scholar
  15. Gruneberg, H. (1962). Genetical studies on the skeleton of the mouse. XXXII. The development of shaker with syndactylism. Genet. Res. 3, 157–166.Google Scholar
  16. Jimenez, S.A., Millan, A., Bashey, R.I. (1984). Scleroderma-like alterations in collagen metabolism occurring in the Tsk (Tight skin) Mouse. Arthritis Rheum. 27, 180–185.Google Scholar
  17. Kainulainen, K., Sakai, L.Y., Child, A., Pope, F.M., Puhakka, L., Ryhanen, L., Palotie, A., Kaitila, I., Peltonen, L. (1992). Two mutations in Marfan syndrome resulting in truncated fibrillin polypeptides. Proc. Natl. Acad. Sci. USA 89, 5917–5921.Google Scholar
  18. Lane, P.W., Eicher, E.M. (1985). The location of plucked (pk) on chromosome 18 of the mouse. J. Hered. 76, 476–477.Google Scholar
  19. Lane, P.W., Searle, A.G., Beechey, C.V., Eicher, E.M. (1981). Chromosome 18 of the mouse. J. Hered. 72, 409–412.Google Scholar
  20. Lee, B., Maurice, G., Emilia, V., Hori, H., Mattei, M., Sarfarazi, M., Tsipouras, P., Ramirez, F., Hollister, D.W. (1991). Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 352, 330–334.Google Scholar
  21. Li, X., Pereira, L., Zhang, H., Sanguineti, C., Ramirez, F., Bonadio, J., Francke, U. (1993). Fibrillin genes map to regions of conserved mouse/human synteny on mouse chromosomes 2 and 18. Genomics 18, 667–672.Google Scholar
  22. Lomedico, P.T., Gubler, U., Hellman, C.P., Dukovich, M., Giri, J.G., Pan, Y.-C.E., Collier, K., Semionow, R., Chua, A.O., Mizel, S.B. (1984). Cloning and expression of murine interleukin-1 cDNA in Escherichia coli. Nature 312, 458–462.Google Scholar
  23. Magenis, R.E., Maslen, C.L., Smith, L., Allen, L., Sakai, L.Y. (1991). Localization of the fibrillin (FBN) gene to chromosome 15, band q21.1. Genomics 11, 346–351.Google Scholar
  24. Majors, J.E., Varnum, H.E. (1981). Nucleotide sequences at host-proviral junctions for mouse mammary tumor virus. Nature 289, 253–258.Google Scholar
  25. Marini, J.C., Nelson, K.K., Battey, J., Siracusa, L.D. (1991). The pituitary hormones arginine vasopressin-neurophysin II and oxytocin-neurophysin I show close linkage with interleukin-1 on mouse chromosome 2. Genomics 15, 200–202.Google Scholar
  26. Martorana, P.A., van Even, P., Gardi, C., Lungarella, G. (1989). A 16-month study of the development of genetic emphysema in tight-skin mice. Am. Rev. Respir. Dis. 139, 226–232.Google Scholar
  27. Menton, D.N., Hess, R.A. (1980). The ultrastructure of collagen in the dermis of tight-skin (Tsk) mutant mice. J. Invest. Dermatol. 74, 139–147.Google Scholar
  28. Menton, D.N., Hess, R.A., Lichtenstein, J.R., Eisen, A.Z. (1978). The structure and tensile properties of the skin of Tight-skin (Tsk) mutant mice. J. Invest. Dermatol. 70, 4–10.Google Scholar
  29. Milewicz, D.M., Pyeritz, R.E., Crawford, E.S., Byers, P.H. (1992). Marfan syndrome: defective synthesis, secretion, and extracellular matrix formation of fibrillin by cultured dermal fibroblasts. J. Clin. Invest. 89, 79–86.Google Scholar
  30. Oakey, R.J., Caron, M.G., Lefkowitz, R.J., Seldin, M.F. (1991) Genomic organization of adrenergic and serotonin receptors in the mouse: linkage mapping of sequence-related genes provides a method for examining mammalian chromosome evolution. Genomics 10, 338–344.Google Scholar
  31. Osborn, T.G., Bauer, N.E., Ross, S.C., Moore, T.L., Zuckner, J. (1983). The tight-skin mouse: physical and biochemical properties of the skin. J. Rheumatol. 10, 793–796.Google Scholar
  32. Osborn, T.G., Bashey, R.I., Moore, T.L., Fischer, V.W. (1987). Collagenous abnormalities in the heart of the tight skin mouse. J. Mol. Cell. Cardiol. 19, 581–587.Google Scholar
  33. Parnes, J.R., Seidman, J.G. (1982). Structure of wild-type and mutant mouse β2-microglobulin genes. Cell 29, 661–669.Google Scholar
  34. Pereira, L., D'Alessio, M., Ramirez, F., Lynch, J.R., Sykes, B., Pangilinan, T., Bonadio, J. (1993). Genomic organization of the sequence coding for fibrillin, the defective gene product in Marfan syndrome. Hum. Mol. Genet. 2, 961–968.Google Scholar
  35. Ramirez, R., Pereira, L., Zhang, H., Lee, B. (1993). The fibrillin-Marfan syndrome connection. BioEssays 15, 589–594.Google Scholar
  36. Rossi, G.A., Hunninghake, G.W., Gadek, J.E., Szapiel, S.V., Kawanami, O., Ferrans, V.J., Crystal, R.G. (1984). Hereditary emphysema in the tight skin mouse. Evaluation of pathogenesis. Am. Rev. Respir. Dis. 129, 850–855.Google Scholar
  37. Sakai, L.Y., Keene, D.R., Engvall, E. (1986). Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J. Cell Biol. 103, 2499–2509.Google Scholar
  38. Schefler, W.C. (1969). Statistics for the Biological Sciences. Reading, Pa.: Addison-Wesley.Google Scholar
  39. Siracusa, L.D., Abbott, C.M. (1993). Mouse Chromosome 2. Mamm. Genome 4 (Suppl.) S31-S46.Google Scholar
  40. Siracusa, L.D., Buchberg, A.M., Copeland, N.G., Jenkins, N.A. (1989). Recombinant inbred strain and interspecific backeross analysis of molecular markers flanking the murine agouti coat color locus. Genetics 122, 669–679.Google Scholar
  41. Siracusa, L.D., Alvord, G.A., Bickmore, W.A., Jenkins, N.A., Copeland, N.G. (1991). Interspecific backcross mice show sex-specific differences in allelic inheritance. Genetics 128, 813–821.Google Scholar
  42. Siracusa L.D., Christner, P., McGrath,R., Mowers, S.D., Nelson, K.K., Jimenez, S.A. (1993). The Tight skin (Tsk) mutation in the mouse, a model for human fibrotic diseases, is tightly linked to the β2-microglobulin gene on Chromosome 2. Genomics 17, 748–751.Google Scholar
  43. Szapiel, S.V., Fulmer, J.D., Hunninghake, G.W., Elson, N.A., Kawanami, O., Ferrans, V.J., Crystal, R.G. (1981). Hereditary emphysema in the tight-skin (Tsk/+) mouse. Am. Rev. Respir. Dis. 123, 680–685.Google Scholar
  44. Trigg, M.J. (1972). Hair growth in mouse mutants affecting coat texture. J. Zool. (Lond.) 168, 165–198.Google Scholar
  45. Tsipouras, P., DelMastro, R., Sarfarazi, M., Lee, B., Vitale, E., Child, A.H., Godfrey, M., Devereux, R.B., Hewett, D., Steinmann, B., Viljoen, D., Sykes, B.C., Kilpatrick, M., Ramirez, F., and the International Marfan Syndrome Collaborative Study (1992). Genetic linkage of the Marfan syndrome,ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5. N. Eng. J. Med. 326, 905–909.Google Scholar
  46. Zhang, H., Apfelroth, S.D., Hu, W., Davis, E.C., Sanguineti, C., Bonadio, J., Mecham, R.P., Ramirez, F. (1994). Structure and expression of Fibrillin-2, a novel microfibrillar component preferentially located in elastic matrices. J. Cell Biol. 124, 855–863.Google Scholar

Copyright information

© Springer-Verlag New York Inc 1994

Authors and Affiliations

  • C. Goldstein
    • 1
  • P. Liaw
    • 1
  • S. A. Jimenez
    • 2
  • A. M. Buchberg
    • 1
  • L. D. Siracusa
    • 1
  1. 1.Department of Microbiology and ImmunologyJefferson Cancer InstitutePhiladelphiaUSA
  2. 2.Department of Medicine, Jefferson Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA

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