Haemophilia B in Female Twins Caused by a Point Mutation in one Factor IX Gene and Nonrandom Inactivation Patterns of the X-Chromosomes

Summary

Haemophilia B is a X-linked recessive bleeding disorder with an incidence of 1:25,000-30,000 male birth. Usually female carriers are clinically normal. Phenotypic expression of the disease in female carriers is extremely rare.

We describe cytogenetically inconspicuous female identical twins both with factor IX levels below 2%, prolonged bleeding after venipuncture as well as haematomas after intramuscular injections. The father, suffering from a severe haemophilia B, is deceased. By sequencing one point mutation was characterized in heterozygote condition in the factor EX gene of the probands at nt 17678. This mutation leads to the substitution cystein 88 to tyrosine in the growth factor domain of the factor IX. Investigation of the X-chromosomal inactivation by comparison of methylation patterns of genomic DNA at locus DXS255 after digestion with Pst I and Pst I +Hha I and hybridisation with the probe M27β indicated a nonrandom pattern of X-chromosomal inactivation in the twins. In both girls, only the paternal X-chromosome was the active one leading to the phenotypic expression of haemophilia in the female carriers.

• References

• 1 Woliina K, Zintl F, Hämophilie beiMädchen. Übersicht eine. Monatsschrift Kinderheilkunde 1996; 14: 830-835
• 2 Clarke JTR, Greer WL, Strasberg PM, Pearce RD, Skoromowski MA, Ray PN. Hunter disease (Mucopolysaccharidosis Type II) associated with unbalanced inactivation of the X-chromosomes in a karyotypically normal girl. Am J Hum Genet 1991; 49: 289-297
• 3 Azofeifa J, Voit T, Hübner Ch, Cremer M. X-chromosome methylation in manifesting and healthy carriers, of dystrophinopaties: concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes. Hum Genet 1995; 96: 167-176
• 4 Aral B, de SaintBasile G, Al-Garawi S, Kamoun P, Ceballos-Picot I. Novel nonsense mutation in the hypoxanthine guanine phosphoribosyl- transferase gene and nonrandom X-inactivation causing Lesch-Nyhan syndrome in a female patient. Hum Mutation 1996; 07: 52-58
• 5 Puck JM, Stewart CC, Nussbaum RL. Maximum likelihood analysis of human T-cell X chromosome inactivation patterns: Normal women versus carriers of X-linked severe combined Immunideficiency. Am J Hum Genet 1992; 50: 742-748
• 6 Wengler G, Gorlin JB, Williamson JM, Rosen FS, Bing DH. Nonrandom inactivation of the X chromosome in early lineage hematopoetic cells in carriers of Wiskott-Aldrich syndrome. Blood 1995; 85: 2471-2477
• 7 Andrejew AN, Korenewskaja MI, Rutberg RA, Dukarevitch MZ, Pokrovskij P, Tokarew YN. Haemophilia A in a patient with testicular feminization. Thromb Diath Haemorrh 1985; 33: 208-211
• 8 Jarczok K, Krawzyk-Kulus M, Molowidin J. Hemophilia in a female with gonadal dysgenesis and XX karyotype. Folia Haematol 1981; 108: 136-140
• 9 Mori PG, Pasino M, Rosanda VC, Bisogni MC, Tonini GP, Scarabicchi SI. Hemophilia A in a 46,i(Xq) female. Brit J Med 1979; 43: 143-147
• 10 Nilsson IM, Berggamann S, Reitalu J, Waldenstrom J. Haemophilia A in a “girl” with male sex chromatin pattern. Lancet 1959; 02: 264-270
• 11 Panarello C, Acquila M, Caorino D, Gimello G, Pecoara M, Mori PG. Concomitant Turner Syndrome and hemophilia in a female with an idic (X) (pl 1) heterozygous at locus DXS52. Cytogenet Cell Genet 1992; 59: 241-242
• 12 Lyon MF. Possible mechanisms of X-chromosome inactivation. Nature New Biol 1971; 232: 229-232
• 13 Belmont JW. Genetic control of X inactivation and processes leading to X-inactivation skewing. Am J Hum Genet 1996; 58: 1101-1108
• 14 Ingerslev J, Schwartz M, Lamm LU, Kruse T, Bukh A, Stjemberg S. Female Haemophilia A in a family with seeming extreme bidirectional lyonization tendency: abnormal premature X-chromosome inactivation?. Clin Genet 1989; 35: 41-48
• 15 Coleman R, Genet SA, Harper JI, Wilkie AOM. Interaction of incontinentia pigmenti and factor VIII mutations in a female with biased X inactivation, resulting in haemophilia. J Med Genet 1993; 30: 497-500
• 16 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. Europ J Haematol 1991; 47: 257-261
• 17 Wadelius C, Lindstedt M, Pigg M, Edberg N, Petterson U, Anvret M. Hemophilia B in a 46, XX female probably caused by non-random X-inac- tivation. Clinical Genetics 1993; 43: 01-04
• 18 Woliina K, Bowen DJ, Syrbe G, Zintl F. Female twins with severe Christmas disease (Hemophilia B). Thromb Haemost 1993; 70: 774-776
• 19 Sambrook J, Fritsch EF, Maniatis T. (eds). Molecular cloning. Cold Spring Harbour Laboratory press; 1989. pp 9.61-9.22
• 20 Anson DS, Choo KH, Rees DJG, Gianelli G, Gould K, Huddleston JA, Brownlee GG. The gene structure of human antihaemophilic factor IX. EMBOJ 1984; 03: 1053-1060
• 21 Mulligan L, Holden JAA, White BN. A DNA marker closely linked to the factor IX (Haemophilia B) gene. Hum Genet 1987; 75: 381-383
• 22 Peake I. Registry of DNA polymorphisms within or close to the factor VIII and factor IX genes. Thromb Haemost 1992; 67: 277-280
• 23 Wulff K, Schröder W, Wehnert M, Herrmann FH. Twenty five novel mutations of the factor IX gene in haemophilia B. HumMut 1995; 06: 346-348
• 24 White MB, Carvalho M, Derse D, O’Brien SJ, Dean M. Detecting single base substitutions as heteroduplex polymorphisms. Genomics 1992; 12: 301-306
• 25 Razin A, Shemer R. DNA methylation in early development. Hum Molec Genet 1995; 04: 1751-1755
• 26 Hendriks RW, Hinds H, Chen ZY, Craig IW. The hypervariable DXS255 locus contains a LINE-1 Repetitive element with a CpG island that is extensively methylated only on the active X-chromosome. Genomics 1992; 14: 598-603
• 27 Fraser NJ, Boyd Y, Craigt I. Isolation and characterization of a human variable copy number tandem repeat at Xcen-pll.22. Genomics 1989; 5: 144-148
• 28 Brown RM, Brown GK. X chromosome inactivation and the diagnosis of X linked disease in females. J Med Genet 1993; 30: 177-184
• 29 Yoshitake S, Schach B, Foster D, Davie EW, Kurachi K. Nucleotide sequence of the gene for Human factor IX (Antihemophilic factor B). Biochemistry. 1985: 3736-3750
• 30 Gianelli F, Green PM, Sommer SS, Poon M-C, Ludwig M, Schwaab R, Reitsma PH, Goossens M, Yoshioka A, Breownlee GG. Haemophilia B (Sixth edition): a database of point mutations and short additions and deletions. Nucleic Acids Research 1996; 24: 103-118
• 31 Revesz T, Schuler D, Goldschmidt B, Elodi S. Christmas disease in one pair of monocygotic twin girls possible effect of lyonization. J Med Genet 1972; 09: 396-399
• 32 Lusher JM, McMillan CW. Severe Factor VIII and factor IX deficiencies in females. Amer J Medicine 1978; 65: 637-648
• 33 Kitchens CS. Discordance in a pair of identical twin carriers of factor IX deficiency. Am J Hematol 1987; 24: 225-230
• 34 Mannucci PM, Coppola R, Lombardi R. Direct proof of extreme Lyonization as a cause of low factor VIII levels in females. Thromb Haemost 1978; 39: 544-545
• 35 Bithell TC, Pizarro S, MacDiarmid WD. Variant of factor IX deficiency in a female with 45, X Turner’s syndrome. Blood 1970; 36: 208-211
• 36 Gilgenkrantz S, Briquel ME, Mandel JL, Oberle I. A case of a female hemophilia with a 46, XXr karyotype studied with X-chromosome cDNA probes. Hum Genet 1986; 72: 1571-1561
• 37 Nisen P, Stamberg J, Ehrenpreis R, Velasco S, Shende A, Engelberg J, Karayalcin G, Waber L. The molecular basis of severe hemophilia in a girl. New Engl J Med 1986; 315: 1139-1142
• 38 Cattanach BM, Raspberry C. Identification of the Mus spretus Xce allele. Mouse Genome 1991; 89: 565-566
• 39 Naumova AK, Plenge RM, Bird LM, Leppert M, Morgan K, Willard HF, Sapienza C. Heretability of X-Chromosome-inactivation phenotype in a large family. Am J Hum Genet 1996; 58 (111) 1-9
• 40 Taylor SAM, Deugan KV, Lillicrap D. 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
• 41 Goodship J, Carter J, Bum J. X-inactivation patterns in monozygotic and dizygotic female twins. Am J Med Genet 1996; 61: 205-208
• 42 Lubinski MS, Hall JG. Genomic imprinting, monocygous twinning, and X-inactivation. Lancet 1991; 337: 1288
• 43 Redonnet-Vemhet I, Ploosvan AmstelJK, Jansen RPM, Wevers RA, Salvayre R, Levade T. Uneven X inactivation in a female monozygotic twin pair with fabry disease and discordant expression of a novel mutation in the α-galactosidase A gene. J Med Genet 1996; 33: 682-688
• 44 Heard E, Avner P. Role play in X-inactivation. Human Molec Genet 1994; 3: 1481-1485
• 45 Migeon B, Jeppesen P, Torchia BS, Fu S, Dunn MA, Axelman J, Schmeck-peper BJ, Fantes J, Zori R, Driscoll D. Lack of X-inactivation associated with maternal X isodisomy: Evidence for counting mechanism prior to X inactivation during human embryogenesis. Am J Hum Genet 1996; 58: 161-170