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.

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.

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 A de novo intragenic deletion of the potential EGF domain of the factor IX gene in a family with severe hemophilia B

Blood ◽  
1986 ◽  
Vol 68 (4) ◽  
pp. 961-963 ◽  
Author(s):  
M Vidaud ◽  
C Chabret ◽  
C Gazengel ◽  
L Grunebaum ◽  
JP Cazenave ◽  
...  
Keyword(s):  
Germ Cells ◽  
Dna Hybridization ◽  
Genomic Dna ◽  
De Novo ◽  
Factor Ix ◽  
Hemophilia B ◽  
Specific Gene ◽  
Severe Hemophilia ◽  
Intragenic Deletion ◽  
Egf Domain

Abstract We have studied a family of three patients who were severely afflicted with hemophilia B without inhibitor for their factor IX genes through the use of factor IX cDNA and genomic DNA probes. The patients had detectable (30% of normal) factor IX antigen. DNA hybridization analysis demonstrated that these patients had a partial intragenic deletion in their factor IX gene. This 2.8-kb deletion included exon d and the surrounding sequences. This exon codes for the amino acid sequence from No. 47 through 84 of the factor IX protein and contains its first potential EGF domain; the de novo occurrence of the mutation in the grandfather's germ cells was established by linkage analysis. This specific gene has been named F IXStrasbourg.

Two Distinct Mutations Cause Severe Hemophilia B in Two Unrelated Canine Pedigrees

1999 ◽  
Vol 82 (10) ◽  
pp. 1270-1275 ◽  
Author(s):  
Weikuan Gu ◽  
James Catalfamo ◽  
Jharna Ray ◽  
Kunal Ray ◽  
Marjory Brooks
Keyword(s):  
Catalytic Domain ◽  
Stop Codon ◽  
Spontaneous Mutation ◽  
Mammalian Species ◽  
Donor Site ◽  
Splice Junction ◽  
Factor Ix ◽  
Hemophilia B ◽  
Acceptor Site ◽  
Plasma Factor

SummaryThe molecular defects causing severe factor IX deficiency were identified in two distinct canine breed-variants. Both defects were associated with an absence of plasma factor IX coagulant activity and antigen. A large deletion mutation was found in 1 breed variant, spanning the entire 5’ region of the factor IX gene extending to exon 6. An approximately 5 kb insertion disrupted exon 8 of the second breed-variant. This insertion was associated with alternative splicing between a donor site 5’ and acceptor site 3’ to the normal exon 8 splice junction, with introduction of a new stop codon. The resultant transcript lacked most of the factor IX catalytic domain and 3’ untranslated region. Molecular analyses of canine hemophilia B define an experimental model for study of inhibitor formation and gene therapy strategies, and provide insight into spontaneous mutation mechanisms in the factor IX gene and on the X chromosome of mammalian species.

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.

Factor IX-Inhibitors

1971 ◽  
Vol 25 (03) ◽  
pp. 447-459 ◽  
Author(s):  
K Lechner
Keyword(s):  
Factor Viii ◽  
Incubation Temperature ◽  
Deae Cellulose ◽  
Factor Ix ◽  
Hemophilia B ◽  
Light Chains ◽  
Severe Hemophilia ◽  
Inhibitor Protein ◽  
Plasma Factor ◽  
Immune Globulins

Summary1. Two patients with severe hemophilia B and an acquired inhibitor against factor IX are described.2. The inhibitors inactivate factor IX irreversibly. The speed of inactivation is very fast and cannot slowed down by dilution of the inhibitor or by lowering of the incubation temperature. Factor IX of serum is inactivated to a higher degree than factor IX of plasma. Factor IX inhibitors are more sensitive to dilution than factor VIII inhibitors.3. The inhibitor protein is eluted from the Sephadex G-200 column with the G-peak. On Chromatography on DEAE-cellulose two activity peaks are obtained.4. Immunologically the inhibitors belong predominantly to the immune globulins of the G-class, but it cannot be excluded that the activity is also associated with IgA. As light chains kappa chains were found in one case.

scholarly journals A Single Base Insertion in F9 Causing Hemophilia B in a Family of Newfoundland–Parti Standard Poodle Hybrid Dogs

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1491
Author(s):  
Henrike Kuder ◽  
Liubov Sandzhieva-Vuzzo ◽  
Alexandra Kehl ◽  
Jonathan M. Rappaport ◽  
Elisabeth Müller ◽  
...  
Keyword(s):  
Stop Codon ◽  
Molecular Genetic ◽  
Genetic Defect ◽  
Clinical Manifestations ◽  
Premature Stop Codon ◽  
Factor Ix ◽  
Hemophilia B ◽  
Surgical Removal ◽  
Standard Poodle ◽  
Plasma Factor

Hemophilia B is an x-linked recessive hereditary coagulopathy that has been reported in various species. We describe a male Newfoundland–Parti Standard Poodle hybrid puppy and its family with hemophilia B from clinical manifestations to the molecular genetic defect. The index case presented for dyspnea was found to have a mediastinal hematoma, while surgical removal and transfusion support brought some relief, progressive hematoma formations led to humane euthanasia. Sequencing the F9 exons revealed a single nucleotide insertion resulting in a frameshift in the last exon (NM_001003323.2:c.821_822insA), predicted to result in a premature stop codon (NP_001003323.1:p.Asn274LysfsTer23) with a loss of 178 of 459 amino acids. The unexpected high residual plasma factor IX activity (3% to 11% of control) was likely erroneous, but no further studies were performed. Both the purebred Newfoundland dam and her sister were heterozygous for the insertion. Five additional male offspring developed severe hemorrhage and were hemizygous for the F9 variant and/or had a prolonged aPTT. In contrast, other male littermates had normal aPTTs and no evidence of bleeding. While they are related to a common Newfoundland granddam, the prevalence of the pathogenic variant in the Newfoundland breed is currently unknown. These clinical to molecular genetic studies illustrate that precision medicine is achievable in clinical companion animal practice.

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.

scholarly journals A de novo intragenic deletion of the potential EGF domain of the factor IX gene in a family with severe hemophilia B

Blood ◽  
1986 ◽  
Vol 68 (4) ◽  
pp. 961-963
Author(s):  
M Vidaud ◽  
C Chabret ◽  
C Gazengel ◽  
L Grunebaum ◽  
JP Cazenave ◽  
...  
Keyword(s):  
Germ Cells ◽  
Dna Hybridization ◽  
Genomic Dna ◽  
De Novo ◽  
Factor Ix ◽  
Hemophilia B ◽  
Specific Gene ◽  
Severe Hemophilia ◽  
Intragenic Deletion ◽  
Egf Domain

We have studied a family of three patients who were severely afflicted with hemophilia B without inhibitor for their factor IX genes through the use of factor IX cDNA and genomic DNA probes. The patients had detectable (30% of normal) factor IX antigen. DNA hybridization analysis demonstrated that these patients had a partial intragenic deletion in their factor IX gene. This 2.8-kb deletion included exon d and the surrounding sequences. This exon codes for the amino acid sequence from No. 47 through 84 of the factor IX protein and contains its first potential EGF domain; the de novo occurrence of the mutation in the grandfather's germ cells was established by linkage analysis. This specific gene has been named F IXStrasbourg.

Three Distinct Point Mutations in the Factor IX Gene of Three Japanese CRM+ Hemophilia B Patients (Factor IX BMNagoya 2, Factor IX Nagoya 3 and 4)

1991 ◽  
Vol 65 (05) ◽  
pp. 514-520 ◽  
Author(s):  
Motohiro Hamaguchi ◽  
Tadashi Matsushita ◽  
Mitsune Tanimoto ◽  
Isao Tekahashi ◽  
Kohji Yamamoto ◽  
...  
Keyword(s):  
Point Mutation ◽  
Calcium Binding ◽  
Point Mutations ◽  
Dna Amplification ◽  
Peptide Bond ◽  
Factor Ix ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Human Factor Ix ◽  
Factor Xia

SummaryEnzymatic DNA amplification and complete sequence analysis were used to investigate human factor IX coding sequences in three CRM+ hemophilia B patients. In a patient with severe hemophilia B and a markedly prolonged ox-brain prothrombin time, a C to T transition in exon VI changed the codon for Argl80 to Trp (factor IX BMNagoya 2). This mutation would impair the cleavage by factor XIa required for activation of the zymogen. In a patient with mild hemophilia B, a G to A transition in exon VI changed the codon for Argl45 to His (factor IX Nagoya 3). This substitution also would be predicted to preclude the cleavage of factor IX by factor XIa at this peptide bond (Argl45-Alal46). Furthermore, this point mutation creates a new NlaIII restriction site which provides a quick and reliable method for carrier detection in the affected family members. A patient with severe hemophilia B (factor IX Nagoya 4) had a G to A transition in exon II changing the codon for Glu21 to Lys. This novel point mutation is assumed to impair the function of factor IX by disrupting the calcium binding of factor IX.

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