An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B

Abstract

lation factor IX provides novel insights into the phenotypes and genetics of hemophilia B. J Thromb Haemost 2013; 11: 1329-40.Summary. Background: Factor IX (FIX) is important in the coagulation cascade, being activated to FIXa on cleavage. Defects in the human F9 gene frequently lead to hemophilia B. Objective: To assess 1113 unique F9 mutations corresponding to 3721 patient entries in a new and up-to-date interactive web database alongside the FIXa protein structure. Methods: The mutations database was built using MySQL and structural analyses were based on a homology model for the human FIXa structure based on closely-related crystal structures. Results: Mutations have been found in 336 (73%) out of 461 residues in FIX. There were 812 unique point mutations, 182 deletions, 54 polymorphisms, 39 insertions and 26 others that together comprise a total of 1113 unique variants. The 64 unique mild severity mutations in the mature protein with known circulating protein phenotypes include 15 (23%) quantitative type I mutations and 41 (64%) predominantly qualitative type II mutations. Inhibitors were described in 59 reports (1.6%) corresponding to 25 unique mutations. Conclusion: The interactive database provides insights into mechanisms of hemophilia B. Type II mutations are deduced to disrupt predominantly those structural regions involved with functional interactions. The interactive features of the database will assist in making judgments about patient management.

Factor IX mutations in hemophilia B patients from Liaoning Province, China

“…Point mutations (single-nucleotide substitutions) were the most common gene defects. This result is consistent with another study, which reported that point mutations are present in approximately 73% of patients with HB [8]. CG transitions can cause missense or nonsense mutations, depending on the codon involved and the types of transition (C-to-T or G-to-A).…”

Mutation Spectrum and Genotype–Phenotype Analyses in a Pakistani Cohort With Hemophilia B

“…These are mostly point mutations (73.0%), missense in the majority of the cases (74.4%). 3 Simultaneous short insertions and deletions (indels) constitute about 1.5% of the mutations, whereas gross gene deletions account for about 16.3% of the cases. Another group of mutations that occur in the promoter region of the FIX gene result in HB Leyden.…”

Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens

“…Although in hemophilia A about 80% of the patients exhibit null mutations with no endogenous FVIII protein synthesis, hemophilia B show only about 20% to 30% null mutations. 66,67 Hemophilia B especially is much more commonly caused by missense mutations, which might be associated with some small amounts of endogenous plasma FIX protein. In their 2010 study, Santagostino and coworkers showed that the type of mutation was the only significant parameter influencing the phenotype.…”