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Characterization of the original Christmas disease mutation (cysteine 206----serine): from clinical recognition to
S A Taylor1, J Duffin, C Cameron
1Department of Pathology, Queen's University, Kingston, Ontario, Canada.
Insights
Christmas disease, a bleeding disorder, is caused by a specific mutation in the factor IX gene. Researchers identified a guanine to cytosine substitution at nucleotide 30,070 in the first patient studied.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Christmas disease, also known as hemophilia B, is a rare inherited bleeding disorder.
- It is characterized by a deficiency in functional coagulation factor IX.
- The disorder was first described in 1952.
Observation:
- The index case of Christmas disease presented with severe factor IX coagulant deficiency and absent factor IX antigen.
- The factor IX gene from this patient was analyzed using the polymerase chain reaction (PCR).
Findings:
- A single nucleotide substitution (guanine to cytosine) was identified at position 30,070 in the factor IX gene.
- This mutation results in an amino acid change from cysteine to serine at position 206 of the factor IX protein.
- This specific mutation is not found in over 200 previously sequenced factor IX genes, indicating its novelty.
Implications:
- The molecular characterization of this novel mutation provides crucial insights into the pathogenesis of Christmas disease.
- Understanding specific genetic defects aids in diagnosing and potentially treating hemophilia B.
- This finding contributes to the growing knowledge base of genetic mutations causing coagulation disorders.
Abstract:
Christmas disease was first reported as a distinct clinical entity in two manuscripts published in 1952. 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. 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.