Summary
It has been suggested that a protein factor causing ciliary dyskinesis is a marker for the basic defect causing cystic fibrosis (CF), and that the structural gene for this protein may be (amongst others) on human chromosome 4. We have isolated two DNA sequences mapping to chromosome 4 which show restriction fragment length polymorphisms (RFLPs), and have followed their segregation in families in which cystic fibrosis occurs. Elevent families with a total of 30 children with CF and ten unaffected sibs were studied. We have also followed the inheritance of RFLPs revealed by two probes mapping to chromosome 4 and obtained from another laboratory, polymorphisms revealed by cloned coding sequences for albumin and fibrinogen, and the inheritance of the MNS blood group. Although the level of albumin is altered in children with CF, the gene does not segregate with CF, and therefore albumin can be excluded as the site of the basic defect. Tight linkage with CF was not found with any of the seven markers investigated, and therefore, assuming that the markers (excepting MNS and fibrinogen) are unlinked to one another, approximately half of the total genetic length of chromosome 4 may be excluded.
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References
Alon N, Riordan SR (1984) Alteration in the major isoelectric forms of serum albumin in cystic fibrosis. In: Lawson D (ed) Proceedings of the Ninth International Cystic Fibrosis Congress. Wiley, Chichester, p 314
Bhattacharya SS, Wright AF, Clayton JF, Price WH, Phillips CI, McKeown CMF, Jay M, Bird AC, Person PC, Southern EM, Evans HJ (1984) Close linkage between X-linked retinitis pigmentosa and a restriction fragment length polymorphism identified by the recombinant DNA probe L1.28. Nature 309:253–255
Botstein D, White RL, Skolnick M, Davies RW (1980) Construction of a genetic linkage map using restriction fragment length polymorphisms. Am J Hum Genet 32:314–331
Bowman BH, Lockhart CH, McCombs ML (1969) Oyster ciliary inhibition by cystic fibrosis factor. Science 164:325
Brock DJH, Haywood C, Super M (1982) Controlled trial of serum isoelectric focusing in the detection of the cystic fibrosis gene. Hum Genet 60:30–31
Chandra RK, Madhavankutty K, Way RC (1975) Serum α-fetoprotein levels in patients with cystic fibrosis and their parents and siblings. Br Med J I:714–716
Davies KE, Gilliam TC, Williamson R (1983) Cystic fibrosis is not caused by a defect in the gene coding for human complement three. Mol Biol Med 1:185–190
Davies KE, Pearson PL, Harper PS, Murray JM, O'Brien T, Sarfarazi M, Williamson R (1983) Linkage analysis of two cloned DNA sequences flanking the Duchenne muscular dystrophy locus on the short arm of the human X chromosome. Nucleic Acids Res 11: 2303–2312
Gilliam TC, Scambler P, Robbins T, Ingle C, Williamson R, Davies KE (1984) The positions of three restriction fragment length polymorphisms on chromosome 4 relative to known genetic markers. Hum Genet 69:154–158
Goodchild MC, Edwards JH, Glen KP, Grindley C, Harris R, Mackintosh P, Wentzel J (1976) A search for linkage in cystic fibrosis. J Med Genet 13:417–419
Griffin W, Rutland J, Cole P (1984) Inhibition of rabbit tracheal ciliary motility by human serum. In: Lawson D (ed) Proceedings of the Ninth International Cystic Fibrosis Congress. Wiley, Chichester, p 197
Gusella JF, Wexler NS, Coneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins PC, Ottina K, Wallace MR, Sakaguchi AY, Young AB, Shoulson I, Bonilla I, Martin JB (1983) A polymorphic DNA marker genetically linked to Huntington's disease. Nature 306:234–238
Hultén MA, Palmer RW, Laurie DA (1982) Chiasma derived maps and recombination fractions: chromosome 1. Ann Hum Genet 46: 167–176
Humphries SE, Iman AMA, Robbins T, Cook M, Carritt B, Ingle C, Williamson R (1984) The regional assignment of the human fibrinogen genes to 4q26-qter and the identification of a DNA polymorphism for α-fibrinogen. Hum Genet 69:148–153
Iman AMA, Eaton MAW, Williamson R, Humphries S (1983) Isolation and characterisation of cDNA clones for the Aα and γ chains of human fibrinogen. Nucleic Acids Res 11:7427–7434
Keats BJB, Morton NE, Rao DC (1981) Reduction of physical assignment to a standard lod table: chromosome 1. Hum Genet 56:353–359
Kunkel LM, Smith KD, Boyer SH, Borgaonkar DS, Wachtel SS, Miller OJ, Breg WR, Jones HW, Rary JM (1977) Analysis of human Y-chromosome reiterated DNA in chromosome variants. Proc Natl Acad Sci USA 74:1245–1249
Lathrop GM, Lalouel JM, Julier C, Ott J (1984) Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci USA 81:3443–3446
Lawson D (ed) (1984) Proceedings of the Ninth International Cystic Fibrosis Congress. Wiley, Chichester
Mayo BJ, Klebe RJ, Barnett DR, Lankford BJ, Bowman BH (1980) Somatic cell genetic studies of the cystic fibrosis mucociliary inhibitor. Clin Genet 18:379–386
Mendelsohn ML, Mayall BH, Bogart E, Moore D, Perry BH (1973) DNA content and DNA based centromeric index of the 24 human chromosomes. Science 179:1126–1129
Morton NE, Lindsten J, Iselius L, Yee S (1982) Data and theory for a revised chiasma map of man. Hum Genet 62:266–270
Murray JM, Davies KE, Harper PS, Meredith L, Muller LR, Goodfellow PN, Williamson R (1982) Linkage relationship of a cloned DNA sequence on the short arm of the X chromosome to Duchenne muscular dystrophy. Nature 300:69–71
Murray JC, Demopulos CM, Lawn RM, Motulsky AG (1983) Molecular genetics of serum albumin. Proc Natl Acad Sci USA 80: 5951–5955
Olaisen B, Teisberg P, Gedde-Dahl T (1982) Fibrinogen gamma chain locus is on chromosome 4 in man. Hum Genet 61:24
Ott J (1974) Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am J Hum Genet 26:588–597
Rigby PWJ, Dieckmann M Rhodes C, Berg PG (1977) Labelling DNA to high specific activity in vitro by nick translation with DNA polymerase I. J Mol Biol 113:237–251
Romeo G (1984) Cystic fibrosis—a single locus disease. In: Lawson D (ed) Proceedings of the Ninth International Cystic Fibrosis Congress. Wiley, Chichester, pp 155–164
Schmoyer IR, Brooks SP, Fischer JF (1972) Isolation and characterisation of a ciliary dyskinetic factor from cystic fibrosis heterozygous serum. Life Sci 11:1037
Solomon E, Bodmer WF (1979) Evolution of the sickle variant gene. Lancet I:923
Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98:503–517
Spock A, Heick HMC, Cress H, Logan WS (1967) Abnormal serum factor in patients with cystic fibrosis of the pancreas. Pediatr Res 1:173
Weitkamp LR (1978) Concerning the linkage relationship of the Gc and MNSs loci. Hum Genet 43:215–220
Weitkamp LR, Rucknagel DL, Gershowitz H (1966) Genetic linkage between structural loci for albumin and group specific complement (GC). Am J Hum Genet 18:559–567
Wilson GB, Fudenberg HH (1977) Ciliary dyskinesis factors in cystic fibrosis and asthma. Nature 266:463
Wilson GB, Fudenberg HH, Jahn TL (1975) Studies on cystic fibrosis using isoelectric focusing: an assay for detection of cystic fibrosis homozygotes and heterozygote carriers in serum. Pediatr Res 9: 635–640
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Scambler, P., Robbins, T., Gilliam, C. et al. Linkage studies between polymorphic markers on chromosome 4 and cystic fibrosis. Hum Genet 69, 250–254 (1985). https://doi.org/10.1007/BF00293035
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DOI: https://doi.org/10.1007/BF00293035