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BACKGROUND AND OBJECTIVES: Hemophilia B is an X-linked recessive, bleeding disorder caused by mutations in the factor IX gene. A wide range of mutations, showing large molecular heterogeneity, has been described in hemophilia B patients. Our study was aimed at characterizing mutations in the factor IX gene in a cohort of North Indian hemophilia B patients. DESIGN AND METHODS: Polymerase chain reaction (PCR) amplification and direct sequencing of all regions of likely functional significance- the coding regions, promoter, the 5' UTR, the splice junctions and parts of the 3' UTR of the factor IX gene was done in 18 families carrying a severe form of hemophilia B. RESULTS: We identified 10 point mutations (including 2 novel ones); one novel deletion and one donor splice site mutation. Recurrence of a nonsense and a missense mutation was observed. The mutation in 3 families could not be characterized. None of the 14 polymorphic positions reported in the Haemophilia B Mutation database in the regions sequenced were polymorphic; herein we report four novel synonymous single base mismatches. One mutation reported to be causative in the database was found to be more likely a non-causal polymorphism. INTERPRETATION AND CONCLUSIONS: Our data confirm the remarkable heterogeneity of the mutational spectrum in hemophilia B among affected families. This is the first mutation report on the disease in the Indo-Aryan population from the Indian subcontinent. Identification of a causative mutation leads to more precise carrier detection than does conventional polymorphism-based linkage analysis. This can effectively be used to establish genotype/ phenotype relationships.

Type

Journal article

Journal

Haematologica

Publication Date

12/2004

Volume

89

Pages

1498 - 1503

Addresses

Functional Genomics Unit, Institute of Genomics and Integrative Biology, CSIR, Delhi, India.

Keywords

Chromosomes, Human, X, Humans, Hemophilia B, Factor IX, RNA Splice Sites, Amino Acid Substitution, Heterozygote Detection, Polymerase Chain Reaction, Sequence Analysis, DNA, DNA Mutational Analysis, Sequence Deletion, Protein Structure, Tertiary, Genetic Heterogeneity, Base Pair Mismatch, Frameshift Mutation, Mutation, Missense, Point Mutation, Polymorphism, Genetic, Exons, India, Female, Male