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. 1991 Jan 1;88(1):39–42. doi: 10.1073/pnas.88.1.39

Somatic mosaicism and female-to-female transmission in a kindred with hemophilia B (factor IX deficiency).

S A Taylor 1, K V Deugau 1, D P Lillicrap 1
PMCID: PMC50743  PMID: 1986380

Abstract

Studies have shown that hemophilia B (Christmas disease; factor IX deficiency) results from many different mutations in the factor IX gene, of which greater than 95% are single nucleotide substitutions. This study has identified a previously unreported form of hemophilia B in a patient who was a somatic mosaic for a guanine-to-cytosine transversion at nucleotide 31,170 in the factor IX gene. This point mutation changes the codon for residue 350 in the catalytic domain of factor IX from a cysteine to a serine. We used differential termination of primer extension to confirm and measure the degree of mosaicism. Our study shows that a varying proportion of cells from hepatic, renal, smooth muscle, and hematopoietic populations possessed normal as well as mutant factor IX sequences. These results indicate that the mutation in this patient occurred either as an uncorrected half-chromatid mutation in the female gamete or as a replication or postreplication error in the initial mitotic divisions of the zygote preceding implantation. In addition, this kindred also contains two females in successive generations who have moderately severe factor IX deficiency. The molecular pathogenesis of this latter phenomenon has been studied and seems to relate to the unaccompanied expression of the mutant factor IX gene consequent upon a second, as yet undefined, genetic event that has prevented inactivation of sequences including the mutant factor IX gene on the X chromosome inherited from the affected male.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bithell T. C., Pizarro A., MacDiarmid W. D. Variant of factor IX deficiency in female with 45, X Turner's syndrome. Blood. 1970 Aug;36(2):169–179. [PubMed] [Google Scholar]
  2. Bradley T. B., Wohl R. C., Petz L. D., Perkins H. A., Reynolds R. D. Possible gonadal mosaicism in a family with hemoglobin Köln. Johns Hopkins Med J. 1980 Jun;146(6):236–240. [PubMed] [Google Scholar]
  3. Byers P. H., Tsipouras P., Bonadio J. F., Starman B. J., Schwartz R. C. Perinatal lethal osteogenesis imperfecta (OI type II): a biochemically heterogeneous disorder usually due to new mutations in the genes for type I collagen. Am J Hum Genet. 1988 Feb;42(2):237–248. [PMC free article] [PubMed] [Google Scholar]
  4. Choo K. H., Gould K. G., Rees D. J., Brownlee G. G. Molecular cloning of the gene for human anti-haemophilic factor IX. Nature. 1982 Sep 9;299(5879):178–180. doi: 10.1038/299178a0. [DOI] [PubMed] [Google Scholar]
  5. Darras B. T., Francke U. A partial deletion of the muscular dystrophy gene transmitted twice by an unaffected male. Nature. 1987 Oct 8;329(6139):556–558. doi: 10.1038/329556a0. [DOI] [PubMed] [Google Scholar]
  6. Gartler S. M., Francke U. Half chromatid mutations: transmission in humans? Am J Hum Genet. 1975 Mar;27(2):218–223. [PMC free article] [PubMed] [Google Scholar]
  7. Giannelli F., Choo K. H., Rees D. J., Boyd Y., Rizza C. R., Brownlee G. G. Gene deletions in patients with haemophilia B and anti-factor IX antibodies. Nature. 1983 May 12;303(5913):181–182. doi: 10.1038/303181a0. [DOI] [PubMed] [Google Scholar]
  8. Gitschier J., Levinson B., Lehesjoki A. E., De La Chapelle A. Mosaicism and sporadic haemophilia: implications for carrier determination. Lancet. 1989 Feb 4;1(8632):273–274. doi: 10.1016/s0140-6736(89)91279-8. [DOI] [PubMed] [Google Scholar]
  9. Gitschier J. Maternal duplication associated with gene deletion in sporadic hemophilia. Am J Hum Genet. 1988 Sep;43(3):274–279. [PMC free article] [PubMed] [Google Scholar]
  10. Green P. M., Bentley D. R., Mibashan R. S., Nilsson I. M., Giannelli F. Molecular pathology of haemophilia B. EMBO J. 1989 Apr;8(4):1067–1072. doi: 10.1002/j.1460-2075.1989.tb03474.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gyllensten U. B., Erlich H. A. Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7652–7656. doi: 10.1073/pnas.85.20.7652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hall J. G. Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet. 1988 Oct;43(4):355–363. [PMC free article] [PubMed] [Google Scholar]
  13. Higuchi M., Kochhan L., Olek K. A somatic mosaic for haemophilia A detected at the DNA level. Mol Biol Med. 1988 Feb;5(1):23–27. [PubMed] [Google Scholar]
  14. Koeberl D. D., Bottema C. D., Buerstedde J. M., Sommer S. S. Functionally important regions of the factor IX gene have a low rate of polymorphism and a high rate of mutation in the dinucleotide CpG. Am J Hum Genet. 1989 Sep;45(3):448–457. [PMC free article] [PubMed] [Google Scholar]
  15. Kurachi K., Davie E. W. Isolation and characterization of a cDNA coding for human factor IX. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6461–6464. doi: 10.1073/pnas.79.21.6461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Levinson B., Lehesjoki A. E., de la Chapelle A., Gitschier J. Molecular analysis of hemophilia A mutations in the Finnish population. Am J Hum Genet. 1990 Jan;46(1):53–62. [PMC free article] [PubMed] [Google Scholar]
  17. Lillicrap D. P., Liddell M. B., Matthews R. J., Peake I. R., Bloom A. L. Comparison of phenotypic assessment and the use of two restriction fragment length polymorphisms in the diagnosis of the carrier state in haemophilia B. Br J Haematol. 1986 Mar;62(3):557–565. doi: 10.1111/j.1365-2141.1986.tb02968.x. [DOI] [PubMed] [Google Scholar]
  18. Maddalena A., Sosnoski D. M., Berry G. T., Nussbaum R. L. Mosaicism for an intragenic deletion in a boy with mild ornithine transcarbamylase deficiency. N Engl J Med. 1988 Oct 13;319(15):999–1003. doi: 10.1056/NEJM198810133191507. [DOI] [PubMed] [Google Scholar]
  19. Montandon A. J., Green P. M., Giannelli F., Bentley D. R. Direct detection of point mutations by mismatch analysis: application to haemophilia B. Nucleic Acids Res. 1989 May 11;17(9):3347–3358. doi: 10.1093/nar/17.9.3347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Nisen P., Stamberg J., Ehrenpreis R., Velasco S., Shende A., Engelberg J., Karayalcin G., Waber L. The molecular basis of severe hemophilia B in a girl. N Engl J Med. 1986 Oct 30;315(18):1139–1142. doi: 10.1056/NEJM198610303151806. [DOI] [PubMed] [Google Scholar]
  21. Pienkos P. T., Shah V. K., Brill W. J. Molybdenum cofactors from molybdoenzymes and in vitro reconstitution of nitrogenase and nitrate reductase. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5468–5471. doi: 10.1073/pnas.74.12.5468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Päbo S. Ancient DNA: extraction, characterization, molecular cloning, and enzymatic amplification. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1939–1943. doi: 10.1073/pnas.86.6.1939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Spinelli A., Schmid W., Straub P. W. Christmas disease (haemophilia B) in a girl with deletion of the short arm of one X-chromosome (functional Turner syndrome). Br J Haematol. 1976 Sep;34(1):129–135. doi: 10.1111/j.1365-2141.1976.tb00181.x. [DOI] [PubMed] [Google Scholar]
  24. Thompson A. R., Bajaj S. P., Chen S. H., MacGillivray R. T. "Founder" effect in different families with haemophilia B mutation. Lancet. 1990 Feb 17;335(8686):418–418. doi: 10.1016/0140-6736(90)90259-8. [DOI] [PubMed] [Google Scholar]
  25. Wood S., McGillivray B. C. Germinal mosaicism in Duchenne muscular dystrophy. Hum Genet. 1988 Mar;78(3):282–284. doi: 10.1007/BF00291677. [DOI] [PubMed] [Google Scholar]
  26. Yoshioka A., Giddings J. C., Thomas J. E., Fujimura Y., Bloom A. L. Immunoassays of factor IX antigen using monoclonal antibodies. Br J Haematol. 1985 Feb;59(2):265–275. doi: 10.1111/j.1365-2141.1985.tb02993.x. [DOI] [PubMed] [Google Scholar]
  27. Yoshitake S., Schach B. G., Foster D. C., Davie E. W., Kurachi K. Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). Biochemistry. 1985 Jul 2;24(14):3736–3750. doi: 10.1021/bi00335a049. [DOI] [PubMed] [Google Scholar]

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