Six Novel and Three Recurrent Mutations in Nine Austrian Patients with Hemophilia B

1994 ◽  
Vol 72 (01) ◽  
pp. 074-077 ◽  
Author(s):  
J Walter ◽  
I Pabinger-Fasching ◽  
H H Watzke
Keyword(s):  
Direct Sequencing ◽  
Point Mutations ◽  
Factor Ix ◽  
Hemophilia B ◽  
Causative Mutation ◽  
Genetic Defects ◽  
Missense Mutations ◽  
Enzymatic Amplification ◽  
Recurrent Mutations ◽  
Polymerase Chain

SummaryIn this report we describe the molecular basis of the factor IX (FIX) deficiency in nine patients with severe (n = 6), moderate (n = 1) or mild (n = 2) hemophilia B. The following genetic defects were identified by enzymatic amplification with the polymerase chain reaction (PCR) and subsequent direct sequencing of all exons and exon-intron-junctions: patient B.B. (FIX “Vienna I”): deletion of nucleotides 6343 to 6362; patient M.H. and W. J. (FIX “Vienna II”): nucleotide 17704 (C to G), Gin 97 to Glu; patient L. K. (FIX “Vienna III”): nucleotide 17761 (C to T), Arg 116 to stop; patient U. A. (FIX “Vienna IV”): nucleotide 10415 (C to G), Pro 55 to Ala; patient H.G. (FIX “Vienna V”): nucleotide 6488 (C to T), Thr 38 to lie; patient H. M. (FIX “Vienna VI”): nucleotide 31276 (G to C), Trp 385 to Cys; patient L. C. (FIX “Vienna VII”): deletion of nucleotide 6700; patient S.F. (FIX “Vienna VIII”): nucleotide 10392 (A to T), Asp 47 to Val. The causative mutation was detected in the FIX gene in each of the nine patients with hemophilia B. There was one small deletion, one point deletion and seven point mutations. The latter include six missense mutations and one nonsense mutation. The mutations in Vienna III, IV and V have already been described in previous studies. The two deletions, Vienna I and Vienna VII have not been reported previously. The genetic defects observed in Vienna II, VI and VIII are novel missense mutations which result in amino acid changes at residues 97,47 and 385, respectively.

scholarly journals Molecular analysis of hemophilia B in Poland: 12 novel mutations of the factor IX gene.

1999 ◽  
Vol 46 (3) ◽  
pp. 721-726 ◽  
Author(s):  
K Wulff ◽  
K Bykowska ◽  
S Lopaciuk ◽  
F H Herrmann
Keyword(s):  
Direct Sequencing ◽  
Point Mutations ◽  
Factor Ix ◽  
Hemophilia B ◽  
Heteroduplex Analysis ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Pcr Products ◽  
Factor Ix Deficiency ◽  
High Degree

We examined the molecular basis of factor IX deficiency in 53 unrelated Polish patients with hemophilia B. Heteroduplex analysis and direct sequencing of polymerase chain reaction (PCR) products were applied to identify the gene defect. Forty-three different point mutations were detected in the factor IX gene of 47 patients. There were 29 missense mutations, 9 nonsense mutations, 4 splice site mutations and 1 point mutation in the promoter region. Twelve mutations were novel. The results of this study emphasize a very high degree of heterogeneity of hemophilia B.

scholarly journals Mutations causing hemophilia B in Algeria: Identification of two novel mutations of the factor 9 gene

2018 ◽  
Vol 19 (1) ◽  
pp. 52-58 ◽  
Author(s):  
ZIDANI ABLA ◽  
YAHIA MOULOUD ◽  
EL MAHMOUDI HEJER ◽  
GOUIDER EMNA ◽  
ABDI MERIEM ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Point Mutations ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Causative Mutation ◽  
Novel Mutations ◽  
Mutation Database ◽  
Wide Range ◽  
The Family

Abla Z, Mouloud Y, Hejer El, Emna G, Abdi Meriem A, Ouarhlent Yamina O, Naouel S. 2018. Mutations causing hemophilia B in Algeria: Identification of two novel mutations of the factor 9 gene. Biodiversitas 19: 52-58. Hemophilia B (HB) (also known as Christmas disease; Christmas is the family name of the first patient.) is an X linked recessive hemorrhagic disorder caused by mutations in factor 9 (F9: is used for the gene) gene that leads to deficient or defective coagulation factor IX (FIX: is used for the protein). The variable phenotype of HB results from wide range of mutations affecting the F9 gene. Our study was aimed at molecular analysis of HB to identify the causative mutation in known patients with HB in a part of Algeria. For genotyping, polymerase chain reaction (PCR) and direct sequencing have been applied to all the essential regions of the F9 gene from 39 Algerian HB patients belonging to 13 unrelated families. We identified 10 different mutations. The identified mutations included 1 duplication and 9 substitutions. In total 9 point mutations were identified, of which 5 are located in exon 8, the hotspot region in the F9 gene. Among the 10 mutations, 2 are novel and not deposited in database sites nor described in recently published articles. The results of this study emphasize the heterogeneity of HB. In summary, our preliminary results will be used to build an Algerian mutation database which would facilitate genetic counseling.

Genetic Basis and Carrier Detection of Hemophilia B of Chinese Origin

1993 ◽  
Vol 69 (03) ◽  
pp. 247-252 ◽  
Author(s):  
Shu-Wha Lin ◽  
Ming-Ching Shen
Keyword(s):  
Amino Acid ◽  
Gene Deletion ◽  
Direct Sequencing ◽  
Screening Method ◽  
Point Mutations ◽  
Factor Ix ◽  
Hemophilia B ◽  
Sscp Analysis ◽  
Amino Acid Residues ◽  
Chinese Origin

SummaryWe have characterized the genetic defects of 17 hemophilia B patients of Chinese origin by means of the polymerase chain reaction (PCR) and direct sequencing. The single-strand conformation polymorphism (SSCP) was used as an initial screening method to analyze the entire coding region and the flanking introns of each individual’s factor IX gene. The abnormal exons were subsequently amplified and the nucleotide sequence determined. Of the 17 patients studied, 16 had single point mutations and one had a gross gene deletion of exons VII and VIII of factor IX. Among these 16 factor IX variants with point mutations 13 were missense and two were nonsense mutations. The remaining one had a nucleotide deleted, resulting in frame shifting at amino acid residue 97. A total of ten novel mutations, including the one with gross gene deletion, are reported in this study which have not been described previously. Five of the remaining seven variants were missense mutations with novel amino acids substituted for residues 127, 132, 180, 207, and 215, respectively. Mutations containing different amino acid residues at those positions have been reported. The last two are variants that have already been described to contain mutations at amino acid residues 333 and 365, respectively. To evaluate the efficiency of SSCP analysis in assessing the mutated exons and to further confirm our results we sequenced the entire exons of all 17 factor IX genes. The mutations detected by SSCP method were indeed the only mutation identified in each factor IX variant. The SSCP analysis and direct sequencing have also allowed us to circumvent the difficulties of carrier determination for Chinese by direct detection of the abnormal factor IX alleles inherited by the females.

Detection of Ten New Mutations by Screening the Gene Encoding Factor IX of Danish Hemophilia B Patients

1995 ◽  
Vol 73 (05) ◽  
pp. 774-778 ◽  
Author(s):  
Marianne Schwartz ◽  
Jørgen Ingerslev ◽  
Elma Scheibel ◽  
Lise Rud Nielsen
Keyword(s):  
Point Mutations ◽  
Splice Site Mutation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Missense Mutations ◽  
Coding Region ◽  
Site Mutation ◽  
Gene Encoding ◽  
Base Pair Deletion ◽  
Wide Range

SummaryHemophilia B is caused by a wide range of mutations. In order to characterize the mutations among patients in Denmark, we have systematically screened the entire coding region, the promoter region and exon flanking sequences of the gene encoding factor IX using single strand conformation and heteroduplex analyses. Patients from 32 different families were examined, and point mutations (23 different) were found in all of them. Ten of the mutations have not been reported by others; they include a splice site mutation, a single base pair deletion, and missense mutations. Notably, the study contains a female patient and a previously described Leyden mutation. In ten families with sporadic cases of hemophilia B, all 10 mothers were found to be carriers. The origin of two of these mutations was established.

scholarly journals Assessment of the F9 genotype-specific FIX inhibitor risks and characterisation of 10 novel severe F9 defects in the first molecular series of Argentinian patients with haemophilia B

2013 ◽  
Vol 109 (01) ◽  
pp. 24-33 ◽  
Author(s):  
Liliana Carmen Rossetti ◽  
Miguel Martín Abelleyro ◽  
Miguel Candela ◽  
Raúl Pérez Bianco ◽  
Miguel de Tezanos Pinto ◽  
...  
Keyword(s):  
Point Mutations ◽  
Bioinformatic Analysis ◽  
Factor Ix ◽  
Causative Mutation ◽  
Control Analysis ◽  
Missense Mutations ◽  
Novel Mutations ◽  
Haemophilia B ◽  
Large Deletions ◽  
Genotype Frequencies

SummaryIn haemophilia B (HB) (factor IX [FIX] deficiency), F9 genotype largely determines clinical phenotype. Aimed to characterise Argentinian families with HB, this study presents F9 genotype frequencies and their specific FIX inhibitor risk and 10 novel F9 mutations. Ninety-one DNA samples from HB patients and relatives were subjected to a new scheme: a primary screen for large deletions, a secondary screen for point mutations using conformation sensitive gel electrophoresis, DNA-sequencing and bioinformatic analysis. Our unbiased HB population (N=52) (77% with severe, 11.5% moderate and 11.5% mild HB) showed 32 missense (61.5%), including three novel mutations predicting specific structural/functional defects in silico, seven nonsense (13.5%) (one novel), five large deletions, four splice including three novel mutations affecting predicted splicing scores, three indels (two novel) and one Leiden mutation. Our comprehensive HB population included five patients with long-lasting FIX inhibitors: three nonsense (p.E35* (novel), p.R75*, p.W240*) and two entire-F9 deletions. Another patient with an indel (p.A26Rfs*14) developed transient inhibitors. A case-control analysis, based on our global prevalence of 3.05% for developing inhibitors in HB revealed that missense mutations were associated with a low risk odds ratio (OR) of 0.05 and a prevalence of 0.39%, whereas nonsense and entire-F9 deletions had significantly higher risks (OR 11.0 and 32.7) and prevalence (14.3% and 44.5%, respectively). Our cost-effective practical approach enabled identification of the causative mutation in all 55 Argentine families with HB, analysis of the molecular pathology of novel F9 defects and determination of mutation-associated FIX inhibitor risks.

Point Mutations in Four Hemophilia B Patients from China

1990 ◽  
Vol 64 (02) ◽  
pp. 302-306 ◽  
Author(s):  
N S Wang ◽  
S H Chen ◽  
A R Thompson
Keyword(s):  
Dna Sequences ◽  
Genomic Dna ◽  
Stop Codon ◽  
Direct Sequencing ◽  
Point Mutations ◽  
Factor Ix ◽  
Hemophilia B ◽  
Chinese Patients ◽  
Severe Hemophilia ◽  
Plasma Factor

SummaryPoint mutations in factor IX genes of four unrelated Chinese patients with hemophilia B have been identified by direct sequencing of amplified genomic DNA fragments. These four mutations occur in exon 8 of the factor IX gene. A C to T transition at nucleotide 30,863 changes codon 248 from Arg (CGA) to a new Stop codon (TGA), described in a previous family as factor IXMalmo3 (Green P M et al., EMBO J 1989; 8: 1067). A G to A transition, at nucleotide 31,051 changes codon 310 from Trp (TGG) to a nonsense or Stop codon (TGA; factor IXchongqing2)- A G to A transition at nucleotide 31,119 changes codon 333 which is for Arg (CGA) in normal factor IX, to one for Gin (CAA) in the variant previously described as factor IXLondon2 (Tsang T C et al., EMBO J 1988; 7: 3009) in a patient with moderately severe hemophilia B. The fourth patient has a novel C to A transversion at nucleotide 31,290, which corresponds to replacement of codon 390 which is for Ala (GCA) in normal factor IX, to one for Glu (GAA) in a patient with moderately severe hemophilia B (factor IXChongqing3)- DNA sequences of amplified fragments from mothers of three showed both their son’s variant and a normal nucleotide at the appropriate position, indicating that they are carriers. The fourth patient’s (factor IXMalmo3) mother, whose DNA was not evaluable, was most probably a carrier because of her low plasma factor IX levels.

Factor IX Gene Analysis In 70 Unrelated Patients with Haemophilia B: Description of 13 New Mutations

1999 ◽  
Vol 82 (11) ◽  
pp. 1437-1442 ◽  
Author(s):  
M. C. Trzeciak ◽  
A. Durin ◽  
G. Pernod ◽  
V. Gay ◽  
C. Ménart ◽  
...  
Keyword(s):  
Denaturing Gradient Gel Electrophoresis ◽  
Direct Sequencing ◽  
Point Mutations ◽  
Factor Ix ◽  
Coagulation System ◽  
Molecular Defect ◽  
Missense Mutations ◽  
Nucleotide Substitutions ◽  
Haemophilia B ◽  
Gradient Gel Electrophoresis

SummarySeventy unrelated patients suffering from haemophilia B have been screened for determining the molecular defect and for evaluating the spectrum of factor IX mutations in the Rhône Alpes region in France. Most patients were characterized with respect to factor IX antigen and factor IX coagulant activity. We have used denaturing gradient gel electrophoresis to obtain a full scanning of the whole coding, promoter, and exon flanking sequences of the factor IX gene. This technique enabled us to determine the molecular defect in 68 out of 70 families (97%), and the mutation was further identified in the two last patients with a direct sequencing of the gene. A total of 2 complete gene deletions in patients with antifactor IX inhibitor, 6 small insertions/ deletions and 62 point mutations were found. Two of these nucleotide substitutions (Arg145His and Ala233Thr) were detected in 21 patients (30%) suggesting the existence of a local founder effect. Thirteen mutations were previously undescribed, including 7 missense mutations. The detection of mutations in patients affected with haemophilia B may shed some light in the structure-function relationship of factor IX molecule within the coagulation system.

Characterization of Genetic Defects of Hemophilia B of Chinese Origin

1991 ◽  
Vol 66 (04) ◽  
pp. 459-463 ◽  
Author(s):  
Shu-Wha Lin ◽  
Ming-Ching Shen
Keyword(s):  
Amino Acid ◽  
Novel Mutation ◽  
Translation Termination ◽  
Direct Sequencing ◽  
Factor Ix ◽  
Hemophilia B ◽  
Genetic Defects ◽  
Antigen Level ◽  
Chinese Origin ◽  
Nucleotide Residue

SummaryTo define the precise genetic defects of hemophilia B of Chinese origin, we have used the polymerase chain reaction (PCR) combined with direct sequencing to analyze the amplified DNA fragments containing the entire coding regions and their flanking introns of the factor IX gene from 6 affected individuals. Among these patients, two are siblings with normal factor IX antigen level (CRM+) yet reduced factor IX clotting activity (28%). Analysis of their factor IX genes revealed a G to A transition at nucleotide residue 10394, which causes substitution of an arginine for a glycine at amino acid residue 48. This is a novel mutation which resides in the first EGF-like domain of factor IX. Studies of two other hemophilia B patients with CRMr phenotypes (factor IX antigen level <35%, and clotting activity <1%), demonstrated a distinct mutation in each individual's factor IX gene. In one case, a guanine to adenine (residue 6365) transition results in replacement of arginine by glutamine at the –4 codon of the propeptide of factor IX. In the other, thymine at 6442 was mutated to cytosine which causes an arginine for cysteine substitution at residue 23. We have also characterized 2 discrete CRM- patients. Both exhibited an identical mutation at nucleotide residue 6460 which generates a translation termination codon (CGA to TGA) at the 29th amino acid. The mutation created a new NlaIII restriction enzyme site which could be used to identify this variant.

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

1992 ◽  
Vol 67 (01) ◽  
pp. 063-065 ◽  
Author(s):  
Sherryl A M Taylor ◽  
Jacalyn Duffin ◽  
Cherie Cameron ◽  
Jerome Teitel ◽  
Bernadette Garvey ◽  
...  
Keyword(s):  
Nucleotide Substitution ◽  
Novel Mutation ◽  
Factor Ix ◽  
Causative Mutation ◽  
Coding Region ◽  
Body Of Knowledge ◽  
Polymerase Chain ◽  
Splice Junctions

SummaryChristmas 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.

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

2017 ◽  
Vol 24 (5) ◽  
pp. 741-748 ◽  
Author(s):  
Muhammad Tariq Masood Khan ◽  
Arshi Naz ◽  
Jawad Ahmed ◽  
Tahir Shamsi ◽  
Shariq Ahmed ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Direct Sequencing ◽  
In Silico Analysis ◽  
Genetic Alterations ◽  
Factor Ix ◽  
Hemophilia B ◽  
Mutation Spectrum ◽  
Coagulation Activity ◽  
Exon 2 ◽  
Novel Variants

This study aimed to (1) identify F9 genetic alterations in patients with hemophilia B (HB) of Pakistani origin and (2) determine the genotype–phenotype relationships in these patients. Diagnosed cases of HB were identified through registries at designated tertiary health-care centers across the country. Consenting patients were enrolled into the study. The factor IX (FIX) coagulation activity (FIX:C) and key clinical features were recorded. Direct sequencing of F9 was carried out in all patients. All the variants identified were analyzed for functional consequences employing in silico analysis tools. Accession numbers from National Center of Biotechnology Information ClinVar database were retrieved for the novel variants. Genotype–FIX:C relationships were determined followed by FIX:C clinical phenotype assessment. A total of 52 patients with HB from 36 unrelated families were identified, which mainly comprised patients with moderate HB (n = 35; 67.3%). Among these, 35 patients from 22 unrelated families could be contacted and enrolled into the study. Missense variants were the most frequent (58.8%), followed by nonsense variants (17.6%). A missense, a short insertion, and a nonsense novel variants in exon 2, 6, and 7, respectively, were also identified. The disease manifested FIX:C heterogeneity in relation to the corresponding mutation in a significant number of cases. Clinical phenotype heterogeneity was also observed in relation to FIX:C-based severity assessment. We concluded that the registered FIX-deficient population of Pakistan mainly comprises moderate HB. F9 mutation spectrum in Pakistani patients with HB is heterogeneous. The HB population of Pakistan manifests a significant amount of genotype–FIX:C and FIX:C–clinical phenotype heterogeneities.

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