Molecular pathology of haemophilia B.
PDF (1.4M)
Journal: 1989/August - EMBO Journal
ISSN: 0261-4189
PUBMED: 2743975
Abstract:
Direct sequencing of amplified genomic DNA has been used to investigate the molecular basis of haemophilia B and thus identify specific amino acids that are essential for maintenance of structure or function of factor IX. Substitution of Cys 336, Asn 120 results in loss of circulating factor IX antigen and deletion of Arg 37 in gross reduction of circulating protein and loss of activity, while substitution of Arg -4, Arg 333, Asp 64 and Pro 55 cause loss of function without marked reduction in protein serum levels. Frameshift or point mutations resulting in marked loss of coding information are found in patients who develop antibodies to administered factor IX. An enhanced rate of mutation is evident at two CpG dinucleotides in the factor IX gene, which accounts for approximately 25% of all point mutations causing haemophilia B known to date. Direct sequencing of mutations also permits, for the first time, rapid and unequivocal prenatal and carrier diagnoses, in all cases, by eliminating the need for informative segregation of markers.
Open in
PUBMED | PMC | Google Scholar | Wikipedia
Relations:
Content
Citations
(64)
References
(28)
Diseases
(1)
Drugs
(3)
Genes
(1)
Organisms
(1)
Processes
(3)
Similar articles
Articles by the same authors
Discussion board
EMBO J 8(4): 1067-1072
PMID: 2743975

Molecular pathology of haemophilia B.

Abstract

Direct sequencing of amplified genomic DNA has been used to investigate the molecular basis of haemophilia B and thus identify specific amino acids that are essential for maintenance of structure or function of factor IX. Substitution of Cys 336, Asn 120 results in loss of circulating factor IX antigen and deletion of Arg 37 in gross reduction of circulating protein and loss of activity, while substitution of Arg -4, Arg 333, Asp 64 and Pro 55 cause loss of function without marked reduction in protein serum levels. Frameshift or point mutations resulting in marked loss of coding information are found in patients who develop antibodies to administered factor IX. An enhanced rate of mutation is evident at two CpG dinucleotides in the factor IX gene, which accounts for approximately 25% of all point mutations causing haemophilia B known to date. Direct sequencing of mutations also permits, for the first time, rapid and unequivocal prenatal and carrier diagnoses, in all cases, by eliminating the need for informative segregation of markers.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.
icon of scanned page 1067
1067
icon of scanned page 1068
1068
icon of scanned page 1069
1069
icon of scanned page 1070
1070
icon of scanned page 1071
1071
icon of scanned page 1072
1072

Images in this article

Image
Image
on p.1068
Image
Image
on p.1070
Image
Image
on p.1070
Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Anson DS, Choo KH, Rees DJ, Giannelli F, Gould K, Huddleston JA, Brownlee GG. The gene structure of human anti-haemophilic factor IX. EMBO J. 1984 May;3(5):1053–1060.[PMC free article] [PubMed] [Google Scholar]
  • Bentley AK, Rees DJ, Rizza C, Brownlee GG. Defective propeptide processing of blood clotting factor IX caused by mutation of arginine to glutamine at position -4. Cell. 1986 May 9;45(3):343–348. [PubMed] [Google Scholar]
  • Chance PF, Dyer KA, Kurachi K, Yoshitake S, Ropers HH, Wieacker P, Gartler SM. Regional localization of the human factor IX gene by molecular hybridization. Hum Genet. 1983;65(2):207–208. [PubMed] [Google Scholar]
  • Cooke RM, Wilkinson AJ, Baron M, Pastore A, Tappin MJ, Campbell ID, Gregory H, Sheard B. The solution structure of human epidermal growth factor. Nature. 327(6120):339–341. [PubMed] [Google Scholar]
  • Coulondre C, Miller JH, Farabaugh PJ, Gilbert W. Molecular basis of base substitution hotspots in Escherichia coli. Nature. 1978 Aug 24;274(5673):775–780. [PubMed] [Google Scholar]
  • Davis LM, McGraw RA, Ware JL, Roberts HR, Stafford DW. Factor IXAlabama: a point mutation in a clotting protein results in hemophilia B. Blood. 1987 Jan;69(1):140–143. [PubMed] [Google Scholar]
  • Foster DC, Rudinski MS, Schach BG, Berkner KL, Kumar AA, Hagen FS, Sprecher CA, Insley MY, Davie EW. Propeptide of human protein C is necessary for gamma-carboxylation. Biochemistry. 1987 Nov 3;26(22):7003–7011. [PubMed] [Google Scholar]
  • Diuguid DL, Rabiet MJ, Furie BC, Liebman HA, Furie B. Molecular basis of hemophilia B: a defective enzyme due to an unprocessed propeptide is caused by a point mutation in the factor IX precursor. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5803–5807.[PMC free article] [PubMed] [Google Scholar]
  • Giannelli F, Choo KH, Rees DJ, Boyd Y, Rizza CR, Brownlee GG. Gene deletions in patients with haemophilia B and anti-factor IX antibodies. Nature. 1983 May 12;303(5913):181–182. [PubMed] [Google Scholar]
  • Gitschier J, Wood WI, Tuddenham EG, Shuman MA, Goralka TM, Chen EY, Lawn RM. Detection and sequence of mutations in the factor VIII gene of haemophiliacs. Nature. 315(6018):427–430. [PubMed] [Google Scholar]
  • Hagen FS, Gray CL, O'Hara P, Grant FJ, Saari GC, Woodbury RG, Hart CE, Insley M, Kisiel W, Kurachi K, et al. Characterization of a cDNA coding for human factor VII. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2412–2416.[PMC free article] [PubMed] [Google Scholar]
  • Harlos K, Holland SK, Boys CW, Burgess AI, Esnouf MP, Blake CC. Vitamin K-dependent blood coagulation proteins form hetero-dimers. Nature. 1987 Nov 5;330(6143):82–84. [PubMed] [Google Scholar]
  • Leytus SP, Foster DC, Kurachi K, Davie EW. Gene for human factor X: a blood coagulation factor whose gene organization is essentially identical with that of factor IX and protein C. Biochemistry. 1986 Sep 9;25(18):5098–5102. [PubMed] [Google Scholar]
  • Leytus SP, Loeb KR, Hagen FS, Kurachi K, Davie EW. A novel trypsin-like serine protease (hepsin) with a putative transmembrane domain expressed by human liver and hepatoma cells. Biochemistry. 1988 Feb 9;27(3):1067–1074. [PubMed] [Google Scholar]
  • Nilsson IM, Berntorp E, Zettervall O. Induction of split tolerance and clinical cure in high-responding hemophiliacs with factor IX antibodies. Proc Natl Acad Sci U S A. 1986 Dec;83(23):9169–9173.[PMC free article] [PubMed] [Google Scholar]
  • Noyes CM, Griffith MJ, Roberts HR, Lundblad RL. Identification of the molecular defect in factor IX Chapel Hill: substitution of histidine for arginine at position 145. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4200–4202.[PMC free article] [PubMed] [Google Scholar]
  • Rees DJ, Rizza CR, Brownlee GG. Haemophilia B caused by a point mutation in a donor splice junction of the human factor IX gene. Nature. 1985 Aug 15;316(6029):643–645. [PubMed] [Google Scholar]
  • Rees DJ, Jones IM, Handford PA, Walter SJ, Esnouf MP, Smith KJ, Brownlee GG. The role of beta-hydroxyaspartate and adjacent carboxylate residues in the first EGF domain of human factor IX. EMBO J. 1988 Jul;7(7):2053–2061.[PMC free article] [PubMed] [Google Scholar]
  • Reitsma PH, Bertina RM, Ploos van Amstel JK, Riemens A, Briët E. The putative factor IX gene promoter in hemophilia B Leyden. Blood. 1988 Sep;72(3):1074–1076. [PubMed] [Google Scholar]
  • Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. [PubMed] [Google Scholar]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467.[PMC free article] [PubMed] [Google Scholar]
  • Schach BG, Yoshitake S, Davie EW. Hemophilia B (factor IXSeattle 2) due to a single nucleotide deletion in the gene for factor IX. J Clin Invest. 1987 Oct;80(4):1023–1028.[PMC free article] [PubMed] [Google Scholar]
  • Schwartz C, Fitch N, Phelan MC, Richer CL, Stevenson R. Two sisters with a distal deletion at the Xq26/Xq27 interface: DNA studies indicate that the gene locus for factor IX is present. Hum Genet. 1987 May;76(1):54–57. [PubMed] [Google Scholar]
  • Spitzer SG, Pendurthi UR, Kasper CK, Bajaj SP. Molecular defect in factor IXBm Lake Elsinore. Substitution of Ala390 by Val in the catalytic domain. J Biol Chem. 1988 Aug 5;263(22):10545–10548. [PubMed] [Google Scholar]
  • Stenflo J, Lundwall A, Dahlbäck B. beta-Hydroxyasparagine in domains homologous to the epidermal growth factor precursor in vitamin K-dependent protein S. Proc Natl Acad Sci U S A. 1987 Jan;84(2):368–372.[PMC free article] [PubMed] [Google Scholar]
  • Tsang TC, Bentley DR, Mibashan RS, Giannelli F. A factor IX mutation, verified by direct genomic sequencing, causes haemophilia B by a novel mechanism. EMBO J. 1988 Oct;7(10):3009–3015.[PMC free article] [PubMed] [Google Scholar]
  • Wallmark A, Ljung R, Nilsson IM. Determination of factor IX allotypes for carrier identification in haemophilia B. Br J Haematol. 1987 Dec;67(4):427–432. [PubMed] [Google Scholar]
  • Yoshitake S, Schach BG, Foster DC, Davie EW, Kurachi K. Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). Biochemistry. 1985 Jul 2;24(14):3736–3750. [PubMed] [Google Scholar]
Division of Medical and Molecular Genetics, UMDS, London, UK.
Division of Medical and Molecular Genetics, UMDS, London, UK.
Copyright notice
Abstract
Direct sequencing of amplified genomic DNA has been used to investigate the molecular basis of haemophilia B and thus identify specific amino acids that are essential for maintenance of structure or function of factor IX. Substitution of Cys 336, Asn 120 results in loss of circulating factor IX antigen and deletion of Arg 37 in gross reduction of circulating protein and loss of activity, while substitution of Arg -4, Arg 333, Asp 64 and Pro 55 cause loss of function without marked reduction in protein serum levels. Frameshift or point mutations resulting in marked loss of coding information are found in patients who develop antibodies to administered factor IX. An enhanced rate of mutation is evident at two CpG dinucleotides in the factor IX gene, which accounts for approximately 25% of all point mutations causing haemophilia B known to date. Direct sequencing of mutations also permits, for the first time, rapid and unequivocal prenatal and carrier diagnoses, in all cases, by eliminating the need for informative segregation of markers.
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.