Download PDF
Thromb Haemost 2000; 83(03): 433-437
DOI: 10.1055/s-0037-1613833
Review Article
Schattauer GmbH

Absence of Correlation between X Chromosome Inactivation Pattern and Plasma Concentration of Factor VIII and Factor IX in Carriers of Haemophilia A and B

Karen Helene Ørstavik
1   From the Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway
,
Elma Scheibel
2   Centre for Haemophilia, University Hospital Rigshospitalet, Copenhagen
,
Jørgen Ingerslev
3   Centre for Haemophilia and Thrombosis, Skejby University Hospital, Århus
,
Marianne Schwartz
4   Section of Clinical Genetics, University Hospital Rigshospitalet, Copenhagen, Denmark
› Author Affiliations
Further Information

Publication History

Received 22 June 1999

Accepted after resubmission 28 October 1999

Publication Date:
14 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Haemophilia A and B are X-linked disorders which are due to a reduced activity of coagulation factor VIII or IX, respectively. Female carriers have a wide range of plasma concentration of factor VIII or factor IX, and may in rare cases have an affected phenotype. In order to investigate if this variation is related to X chromosome inactivation, we determined the X inactivation pattern in 31 haemophilia A and 15 haemophilia B carriers, using a PCR in the androgen receptor locus in blood DNA. Seven of the haemophilia A carriers and none of the haemophilia B carriers had a skewed pattern (≥80:20). One of the skewed haemophilia A carriers had a low plasma concentration of factor VIII (0.15 U/ml), but the remaining 6 carriers did not differ in factor VIII concentration from that of carriers with a random X inactivation pattern. One carrier with a high factor VIII concentration (2.0 U/ml) did not have a skewed pattern. Similarly, for the haemophilia B carriers, there was no tendency to a more skewed X inactivation pattern in the carriers with low or high factor IX concentrations. In addition, we analysed a female with haemophilia B who was heterozygous for the mutation R180W in the factor IX gene. She had a random X chromosome inactivation pattern. We conclude that the wide range in plasma concentration of factor VIII and factor IX in haemophilia A and B carriers cannot in general be explained by the X chromosome inactivation pattern in peripheral blood cells.

Keywords

Haemophilia - X chromosome inactivation - carrier - female
 

  • References

  • 1 Veltkamp JJ, Meilof J, Remmelts HG, van der Vlerk D, Loeliger EA. Detection of the carrier state in hereditary coagulation disorders. II. Thrombosis et Diathesis Haemorrhagica 1968; 19: 403-22.
    PubMedSearch in Google Scholar
  • 2 Ørstavik KH, Veltkamp JJ, Bertina RM, Hermans J. Detection of carriers of haemophilia B. Brit J Haematol 1979; 42: 293-301.
    CrossrefPubMedSearch in Google Scholar
  • 3 Lyon M. Gene action in the X chromosome of the mouse (Mus musculus L.). Nature 1961; 190: 372-3.
    CrossrefPubMedSearch in Google Scholar
  • 4 Ingerslev J, Schwartz M, Lamm LU, Kruse TA, Bukh A, Stenbjerg S. Female haemophilia A in a family with seeming extreme bidirectional lyonization tendency: abnormal premature X-chromosome inactivation?. Clin Genet 1989; 35: 41-8.
    PubMedSearch in Google Scholar
  • 5 Nisen PD, Waber PG. Nonrandom X chromosome DNA methylation patterns in hemophilia females. J Clin Invest 1989; 83: 1400-3.
    CrossrefPubMedSearch in Google Scholar
  • 6 Taylor SAM, Deugau KV, Lillicrap DP. Somatic mosaicism and female to female transmission in a kindred with hemophilia B (factor IX deficiency). Proc Natl Acad Sci USA 1991; 88: 39-42.
    CrossrefPubMedSearch in Google Scholar
  • 7 Kling S, Coffey AJ, Ljung R, Sjorin E, Nilsson IM, Holmberg L, Gianelli F. Moderate haemophilia B in a female carrier caused by preferential inactivation of the paternal X-chromosome. Eur J Haematol 1991; 47: 257-61.
    PubMedSearch in Google Scholar
  • 8 Wadelius C, Lindstedt M, Pigg M, Egberg N, Pettersson U, Anvret M. Hemophilia B in a 46 XX female probably caused by non-random X inactivation. Clin Genet 1993; 43: 1-4.
    CrossrefPubMedSearch in Google Scholar
  • 9 Acquila M, Caprino D, Bicocchi P, Mori PG, Tagliaferri AR. A skewed Lyonization phenomenon as cause of hemophilia A in a female patient. Blood 1995; 85: 599-600.
    CrossrefPubMedSearch in Google Scholar
  • 10 Ørstavik KH, Ørstavik RE, Schwartz M. Skewed X chromosome inactivation in a female with hemophilia B and in her healthy daughter – a genetic influence on X chromosome inactivation?. J Med Genet 1999; 36: 865-6.
    PubMedSearch in Google Scholar
  • 11 Schröder W, Wulff K, Wollina K, Herrmann FH. Haemophilia B in female twins caused by a point mutation in one factor IX gene and nonrandom inactivation patterns of the X-chromosomes. Thromb Haemost 1997; 78: 1347-51.
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Ørstavik KH, Ørstavik RE, Naumova AD, Adamo PA, Gedeon A, Bolhuis BA, Barth PG, Toniolo D. X chromosome inactivation in carriers of Barth syndrome. Am J Hum Genet 1998; 63: 1457-63.
    CrossrefPubMedSearch in Google Scholar
  • 13 Rud LNielsen, Scheibel E, Ingerslev J, Schwartz M. Detection of ten new mutations by screening the gene encoding factor IX of Danish hemophilia B patients. Thromb Haemost 1995; 73: 774-8.
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 1992; 51: 1229-39.
    PubMedSearch in Google Scholar
  • 15 Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, Millasseau P, Marc S, Bernardi G, Lathrop M, Weissenbach J. The 1993-94 Genethon human genetic linkage map. Nat Genet 1994; 07: 246-339.
    CrossrefPubMedSearch in Google Scholar
  • 16 Busque L, Mio R, Mattioli J, Brais E, Blais N, Lalonde Y, Maragh M, Gilliand DG. Non-random X-inactivation patterns in normal females: Lyonization ratios vary with age. Blood 1996; 88: 59-65.
    CrossrefPubMedSearch in Google Scholar
  • 17 Tan SS, Williams EA, Tam PP. X-chromosome inactivation occurs at different times in different tissues of the post-implantation mouse embryo. Nat Genet 1993; 03: 170-4.
    CrossrefPubMedSearch in Google Scholar
  • 18 Gale RE, Weadon H, Boulos P, Linch DC. Tissue specificity of X-chromosome inactivation pattern. Blood 1994; 83: 2899-905.
    PubMedSearch in Google Scholar
  • 19 Carrel L, Hunt PA, Willard HF. Tissue and lineage-specific variation in inactive X chromosome expression of the murine Smcx gene. Hum Mol Genet 1996; 05: 1361-6.
    CrossrefPubMedSearch in Google Scholar
  • 20 Ørstavik KH, Magnus P, Reisner H, Berg K, Graham JB, Nance W. Factor VIII and factor IX in a twin population. Evidence for a major effect of ABO locus on factor VIII level. Am J Hum Genet 1985; 37: 89-101.
    PubMedSearch in Google Scholar
  • 21 Ørstavik KH, Kornstad L, Reisner H, Berg K. Possible effect of Secretor locus on plasma concentration of factor VIII and von Willebrand factor. Blood 1989; 73: 990-3.
    PubMedSearch in Google Scholar
  • 22 Kerr CB, Preston AE, Barr A, Biggs R. Further studies on the inheritance of factor VIII. Br J Haematol 1996; 12: 212-33.
    PubMedSearch in Google Scholar
  • 23 Graham JB. Genetic control of factor VIII. Lancet 1980; i: 340-2.
    PubMedSearch in Google Scholar
  • 24 Filippi G, Mannucci PM, Coppola R, Farris A, Rinaldi A, Siniscalco M. Studies on hemophilia A in Sardinia bearing on the problems of multiple allelism, carrier detection, and differential mutation rate in the two sexes. Am J Hum Genet 1984; 36: 44-71.
    PubMedSearch in Google Scholar
  • 25 Fearon ER, Kohn DB, Winkelstein JA, Vogelstein B, Blaese RM. Carrier detection in Wiskott-Aldrich syndrome. Blood 1988; 72: 1735-9.
    PubMedSearch in Google Scholar
  • 26 Gibbons RJ, Suthers GK, Wilkie OM, Buckle VJ, Higgs DR. X-linked α-thalassemia/mental retardation (ATR-X) syndrome: Localization to Xq12-q21.31 by X inactivation and linkage analysis. Am J Hum Genet 1992; 51: 1136-49.
    PubMedSearch in Google Scholar
  • 27 Friedrich U, Warburg M, Jørgensen AL. X-inactivation pattern in carriers of X-linked retinitis pigmentosa: a valuable means of prognostic evaluation?. Hum Genet 1993; 92: 359-63.
    CrossrefPubMedSearch in Google Scholar
  • 28 Tihy F, Vogt N, Recan D, Malfoy B, Leturcq F, Coquet M, Serville F, Fontan D, Guillard JM, Kaplan JC, Dutrillaux B, Lemieux N. Skewed inactivation of an X chromosome deleted at the dystrophin gene in an asymptomatic mother and her affected daughter. Hum Genet 1994; 93: 563-7.
    PubMedSearch in Google Scholar
  • 29 Yoshioka M, Yorifuji T, Mituyoshi I. Skewed X inactivation in manifesting carriers of Duchenne muscular dystrophy. Clin Genet 1998; 53: 102-7.
    PubMedSearch in Google Scholar
  • 30 Pegoraro E, Schimke RN, Arahara K, Hayashi Y, Stern H, Marks H, Glasberg MR, Carrol JE, Taber JW, Wessel HB, Bauserman SC, Marks WA, Toriello HV, Higgins JV, Appleton S, Schwatz L, Garcia CA, Hoffman EP. Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females. Am J Hum Genet 1994; 54: 989-1003.
    PubMedSearch in Google Scholar
  • 31 Azofeifa J, Voit T, Hübner C, Cremer M. X chromosome methylation in manifesting and healthy carriers of dystrophinopathies: concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes. Hum Genet 1995; 96: 167-76.
    CrossrefPubMedSearch in Google Scholar
  • 32 Matthews PM, Benjamin D, van Bakel I, Squier MV, Nicholson LVB, Sewry C, Barnes PRJ, Hopkin J, Brown R, Hilton-Jones D, Boyd Y, Karpati G, Brown GK, Craig IW. Muscle X inactivation patterns and dystrophin expression in Duchenne muscular dystrophy carriers. Neuromusc Disord 1995; 05: 209-20.
    CrossrefPubMedSearch in Google Scholar
  • 33 Sumita DR, Vainzof M, Campiotto S, Cerqueira AM, Canovas M, Otto PA, Passos-Buenos MR, Satz M. Absence of correlation between skewed X inactivation in blood and serum creatine-kinase levels in Duchenne/Becker female carriers. Am J Med Genet 1998; 80: 356-61.
    CrossrefPubMedSearch in Google Scholar
  • 34 Watkiss E, Webb T, Bundey S. Is skewed X inactivation responsible for symptoms in female carriers for adrenoleukodystrophy?. J Med Gen 1993; 30: 651-4.
    CrossrefPubMedSearch in Google Scholar
  • 35 Plenge RM, Hendrich BD, Schwartz C, Arena JF, Naumova A, Sapienza C, Winter RM, Willard HF. A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation. Nat Genet 1997; 17: 353-6.
    CrossrefPubMedSearch in Google Scholar
  • 36 Naumova AK, Olien L, Bird LM, Smith M, Verner AE, Leppert M, Morgan K, Sapienza C. Genetic mapping of X-linked loci involved in skewing of X chromosome inactivation in the human. Eur J Hum Genet 1998; 06: 552-62.
    CrossrefPubMedSearch in Google Scholar
  • 37 Reddy BK, Anandavalli TE, Reddi OS. X-linked Duchenne muscular dystrophy in an unusual family with manifesting carriers. Hum Genet 1984; 67: 460-2.
    CrossrefPubMedSearch in Google Scholar
  • 38 Hoffman EP, Pegoraro E. Skewed X inactivation can be inherited as a Mendelian trait in humans. Am J Hum Genet 1995; (Suppl. 57) A49.
    PubMedSearch in Google Scholar
  • 39 Naumova AK, Plenge RM, Bird LM, Leppert M, Morgan K, Willard HF, Sapienza C. Heritability of X chromosome inactivation phenotype in a large family. Am J Hum Genet 1996; 58: 1111-9.
    PubMedSearch in Google Scholar
  • 40 Tanner SM, Ørstavik KH, Kristiansen M, Lev D, Lerman-Sagie T, Sadeh M, Liechti-Gallati S. Skewed X inactivation in a manifesting carrier of X-linked myotubular myopathy, and in her non-manifesting carrier mother. Hum Genet 1999; 104: 249-53.
    CrossrefPubMedSearch in Google Scholar