Heterogeneity of the Factor IX Locus in Nine Hemophilia B Inhibitor Patients

Overview

Journal J Clin Invest

Specialty General Medicine

Date 1987 Mar 1

PMID 3029178

Citations 5

Authors

R J Matthews

D S Anson

I R Peake

A L Bloom

Affiliations

Soon will be listed here.

Abstract

DNA from nine hemophilia B patients who produce anti-factor IX inhibitors (antibodies), including two brothers, was analyzed by the Southern blotting method and hybridization with factor IX cDNA, intragenomic, and 3'-flanking probes. Two inhibitor patients were shown to have total deletions of the factor IX gene. Two other inhibitor patients, the brothers, were shown to have a presumably identical complex rearrangement of the factor IX gene involving two separate deletions. The first deletion is of approximately 5.0 kb and removes exon e. The second deletion is between 9 and 29 kb and removes exons g and h but leaves exon f intact. An abnormal Taq I fragment at one end of the deletion junctions acted as a marker for the inheritance of hemophilia B in the patients' family. Five other inhibitor patients have a structurally intact factor IX gene as detected by this method. Our studies indicate that whereas large structural factor IX gene defects predispose hemophilia B patients to developing an anti-factor IX inhibitor, the development of an inhibitor can be associated with other defects of the factor IX gene.

Citing Articles

Carrier detection through the use of abnormal deletion junction fragments in a case of haemophilia B involving complete deletion of the factor IX gene.

Matthews R, Peake I, Bloom A, Anson D J Med Genet. 1988; 25(11):779-80.

PMID: 2907054 PMC: 1051585. DOI: 10.1136/jmg.25.11.779.

Molecular studies of haemophilia B in Sweden. Identification of patients with total deletion of the factor IX gene and without inhibitory antibodies.

Wadelius C, Blomback M, Pettersson U Hum Genet. 1988; 81(1):13-7.

PMID: 2848757 DOI: 10.1007/BF00283721.

A complete deletion of the factor IX gene and new TaqI variant in a hemophilia B kindred.

Taylor S, Lillicrap D, Blanchette V, Giles A, Holden J, White B Hum Genet. 1988; 79(3):273-6.

PMID: 2841226 DOI: 10.1007/BF00366250.

Identification of a single nucleotide C-to-T transition and five different deletions in patients with severe hemophilia B.

Ludwig M, Schwaab R, Eigel A, Horst J, Egli H, Brackmann H Am J Hum Genet. 1989; 45(1):115-22.

PMID: 2741941 PMC: 1683389.

Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.

Bernstein H, Bishop D, Astrin K, Kornreich R, Eng C, Sakuraba H J Clin Invest. 1989; 83(4):1390-9.

PMID: 2539398 PMC: 303833. DOI: 10.1172/JCI114027.

References

Southern E . Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975; 98(3):503-17. DOI: 10.1016/s0022-2836(75)80083-0. View

Lehrman M, Russell D, Goldstein J, Brown M . Exon-Alu recombination deletes 5 kilobases from the low density lipoprotein receptor gene, producing a null phenotype in familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1986; 83(11):3679-83. PMC: 323586. DOI: 10.1073/pnas.83.11.3679. View

Rigby P, Dieckmann M, Rhodes C, Berg P . Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. J Mol Biol. 1977; 113(1):237-51. DOI: 10.1016/0022-2836(77)90052-3. View

Jones R, Old J, Trent R, Clegg J, Weatherall D . Major rearrangement in the human beta-globin gene cluster. Nature. 1981; 291(5810):39-44. DOI: 10.1038/291039a0. View

Choo K, Gould K, Rees D, Brownlee G . Molecular cloning of the gene for human anti-haemophilic factor IX. Nature. 1982; 299(5879):178-80. DOI: 10.1038/299178a0. View

Kurachi K, Davie E . Isolation and characterization of a cDNA coding for human factor IX. Proc Natl Acad Sci U S A. 1982; 79(21):6461-4. PMC: 347146. DOI: 10.1073/pnas.79.21.6461. View

Giannelli F, Choo K, Rees D, Boyd Y, Rizza C, Brownlee G . Gene deletions in patients with haemophilia B and anti-factor IX antibodies. Nature. 1983; 303(5913):181-2. DOI: 10.1038/303181a0. View

Jaye M, de la Salle H, Schamber F, Balland A, Kohli V, Findeli A . Isolation of a human anti-haemophilic factor IX cDNA clone using a unique 52-base synthetic oligonucleotide probe deduced from the amino acid sequence of bovine factor IX. Nucleic Acids Res. 1983; 11(8):2325-35. PMC: 325887. DOI: 10.1093/nar/11.8.2325. View

Feinberg A, Vogelstein B . A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983; 132(1):6-13. DOI: 10.1016/0003-2697(83)90418-9. View

10.

Vanin E, Henthorn P, Kioussis D, Grosveld F, SMITHIES O . Unexpected relationships between four large deletions in the human beta-globin gene cluster. Cell. 1983; 35(3 Pt 2):701-9. DOI: 10.1016/0092-8674(83)90103-4. View

11.

Chance P, Dyer K, Kurachi K, Yoshitake S, Ropers H, Wieacker P . Regional localization of the human factor IX gene by molecular hybridization. Hum Genet. 1983; 65(2):207-8. DOI: 10.1007/BF00286666. View

12.

Camerino G, Grzeschik K, Jaye M, de la Salle H, Tolstoshev P, Lecocq J . Regional localization on the human X chromosome and polymorphism of the coagulation factor IX gene (hemophilia B locus). Proc Natl Acad Sci U S A. 1984; 81(2):498-502. PMC: 344705. DOI: 10.1073/pnas.81.2.498. View

13.

Giannelli F, Anson D, Choo K, Rees D, Winship P, Ferrari N . Characterisation and use of an intragenic polymorphic marker for detection of carriers of haemophilia B (factor IX deficiency). Lancet. 1984; 1(8371):239-41. DOI: 10.1016/s0140-6736(84)90122-3. View

14.

Peake I, Furlong B, Bloom A . Carrier detection by direct gene analysis in a family with haemophilia B (factor IX deficiency). Lancet. 1984; 1(8371):242-3. DOI: 10.1016/s0140-6736(84)90123-5. View

15.

Anson D, Choo K, Rees D, Giannelli F, Gould K, HUDDLESTON J . The gene structure of human anti-haemophilic factor IX. EMBO J. 1984; 3(5):1053-60. PMC: 557470. DOI: 10.1002/j.1460-2075.1984.tb01926.x. View

16.

Boyd Y, Buckle V, Munro E, Choo K, MIGEON B, Craig I . Assignment of the haemophilia B (factor IX) locus to the q26-qter region of the X chromosome. Ann Hum Genet. 1984; 48(2):145-52. DOI: 10.1111/j.1469-1809.1984.tb01009.x. View

17.

Shapiro S . Genetic predisposition to inhibitor formation. Prog Clin Biol Res. 1984; 150:45-55. View

18.

Hassan H, Orlando M, Leonardi A, Chelucci C, Guerriero R, Mannucci P . Intragenic Factor IX restriction site polymorphism in hemophilia B variants. Blood. 1985; 65(2):441-3. View

19.

Yoshioka A, Giddings J, Thomas J, Fujimura Y, Bloom A . Immunoassays of factor IX antigen using monoclonal antibodies. Br J Haematol. 1985; 59(2):265-75. DOI: 10.1111/j.1365-2141.1985.tb02993.x. View

20.

Mattei M, Baeteman M, Heilig R, Oberle I, Davies K, Mandel J . Localization by in situ hybridization of the coagulation factor IX gene and of two polymorphic DNA probes with respect to the fragile X site. Hum Genet. 1985; 69(4):327-31. DOI: 10.1007/BF00291650. View