Characterization of the Original Christmas Disease Mutation (Cysteine 206 → Serine): From Clinical Recognition to Molecular Pathogenesis

 

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Summary

Christmas disease was first reported as a distinct clinical entity in two manuscripts published in 1952 (1, 2). The eponym associated with this disorder, is the surname of the first patient examined in detail and reported by Biggs and colleagues in a paper describing the clinical and laboratory features of seven affected individuals (3). This patient has severe factor IX coagulant deficiency (less than 0.01 units/ml) and no detectable circulating factor IX antigen (less than 0.01 units/ml). Coding sequence and splice junctions of the factor IX gene from this patient have been amplified in vitro through the polymerase chain reaction (PCR). One nucleotide substitution was identified at nucleotide 30,070 where a guanine was replaced by a cytosine. This mutation alters the amino acid encoded at position 206 in the factor IX protein from cysteine to serine. The non conservative nature of this substitution, the absence of this change in more than 200 previously sequenced factor IX genes and the fact that the remainder of the coding region of this gene was normal, all provide strong circumstantial evidence in favour of this change being the causative mutation in this patient. The molecular characterization of this novel mutation in the index case of Christmas disease, contributes to the rapidly expanding body of knowledge pertaining to Christmas disease pathogenesis.

• References

• 1 Schulman I, Smith CH. Hemorrhagic disease in an infant due to deficiency of a previously undescribed clotting factor. Blood 1952; 7: 794-807
  PubMedGoogle Scholar
• 2 Aggeler PM, White SG, Glendening MB, Page EW, Leake TB, Bates G. Plasma thromboplastin component (PTC) deficiency: a new disease resembling hemophilia. Proc Soc Exp Biol Med 1952; 79: 692-694
  CrossrefPubMedGoogle Scholar
• 3 Biggs R, Douglas AS, Macfarlane RG, Dacie JV, Pitney WR, Merskey C, O’Brien JR. Christmas disease: a condition previously mistaken for haemophilia. Br J Med 1952; 2: 1378-1382
  CrossrefPubMedGoogle Scholar
• 4 Giannelli F, Choo KH, Rees DJG, Boyd Y, Rizza CR, Brownlee GG. Gene deletions in patients with haemophilia B and anti-factor IX antibodies. Nature 1983; 303: 181-182
  CrossrefPubMedGoogle Scholar
• 5 Thompson AR. Structure, function, and molecular defects of factor IX. Blood 1986; 67: 565-572
  PubMedGoogle Scholar
• 6 Giddings JC. The investigation of hereditary coagulation disorders. In: A practical guide to blood coagulation and haemostasis. Thomson JM. (ed). Churchill Livingstone; Edinburgh: 1988. pp 117-157
  Google Scholar
• 7 Yoshioka A, Giddings JC, Thomas JE, Fujimura Y, Bloom AL. Immunoassays of Factor IX Antigen using monoclonal antibodies. Br J Haematol 1985; 59: 265-269
  CrossrefPubMedGoogle Scholar
• 8 Lillicrap DP, Liddell MB, Matthews RJ, Peake IR, Bloom AL. 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; 62: 557-565
  CrossrefPubMedGoogle Scholar
• 9 Gyllenstein UB, Erlich HA. Generation of single stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc Natl Acad Sei USA 1988; 85: 7652-7656
  CrossrefPubMedGoogle Scholar
• 10 Brinkhous KM. A short history of hemophilia, with some comments on the word “hemophilia”. In: Handbook of Hemophilia. Brinkhous KM, Hemker HC. (eds). Elsevier; New York: 1975. pp 3-20
  Google Scholar
• 11 von Koller F, Krusi G, Luchsinger P. Über eine besondere Form hämorrhagischer Diathese. Schweiz Med Wochenschr 1950; 80: 1101-1120
  PubMedGoogle Scholar
• 12 Choo KH, Gould KG, Rees DJG, Brownlee GG. Molecular cloning of the gene for human anti-haemophilia factor IX. Nature 1982; 299: 178-180
  CrossrefPubMedGoogle Scholar
• 13 Kurachi K, Davie EW. Isolation and characterisation of a cDNA coding for human factor IX. Proc Natl Acad Sei USA 1982; 79: 6461-6464
  CrossrefPubMedGoogle Scholar
• 14 Yoshitake S, Schach BG, Foster DC, Davie EW, Kurachi W. Nucleotide sequence of the gene for human factor IX (anti-haemophilic factor B). Biochem J 1985; 24: 3736-3750
  CrossrefPubMedGoogle Scholar
• 15 Giannelli F, Choo KH, Winship PR. Characterisation and use of an intragenic polymorphic marker for detection of carriers of haemophilia B (factor IX deficiency). Lancet 1984; 1: 239-241
  PubMedGoogle Scholar
• 16 Bröcker-Vriends AHJT, Briët E, Quadt R, Bertina RM, van der Linden IK, van der Kamp JJ, Pearson PL, Veitkamp JJ. Carrier detection of haemophilia B by using an intragenic restriction fragment length polymorphism. Thromb Haemostas 1985; 54: 506-509
  PubMedGoogle Scholar
• 17 Tsang TC, Bentley DR, Nilsson I-M, Giannelli F. The use of DNA amplification for genetic counselling related diagnosis in haemophilia B. Thromb Haemostas 1989; 61: 343-347
  PubMedGoogle Scholar
• 18 Bottema CDK, Koeberl DD, Sommer SS. Direct carrier testing in 14 families with haemophilia B. Lancet 1989; 2: 526-529
  PubMedGoogle Scholar
• 19 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; 239: 487-491
  CrossrefPubMedGoogle Scholar
• 20 Koeberl DD, Bottema CDK, Buerstedde J-M, Sommer SS. 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; 45: 448-457
  PubMedGoogle Scholar
• 21 Giannelli F, Green PM, High KA, Lozier JN, Lillicrap DP, Ludwig M, Olek K, Reitsma PH, Goossens M, Yoshioka A, Sommer S, Brownlee GG. Haemophilia B: Database of point mutations and short additions and deletions. Nucleic Acids Res 1990; 18: 4053-4059
  CrossrefPubMedGoogle Scholar