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 The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene

Blood ◽  
1995 ◽  
Vol 86 (10) ◽  
pp. 3797-3804 ◽  
Author(s):  
Q Zhu ◽  
M Zhang ◽  
RM Blaese ◽  
JM Derry ◽  
A Junker ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Point Mutations ◽  
Gene Mutations ◽  
Exon Skipping ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Site Mutation ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Was Gene

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, and immunodeficiency. Besides the classic WAS phenotype, there is a group of patients with congenital X-linked thrombocytopenia (XLT) who have small platelets but only transient eczema, if any, and minimal immune deficiency. Because the gene responsible for WAS has been sequenced, it was possible to correlate the WAS phenotypes with WAS gene mutations. Using a fingerprinting screening technique, we determined the approximate location of the mutation in 13 unrelated WAS patients with mild to severe clinical symptoms. Direct sequence analysis of cDNA and genomic DNA obtained from patient-derived cell lines showed 12 unique mutations distributed throughout the WAS gene, including insertions, deletions, and point mutations resulting in amino acid substitutions, termination, exon skipping, or splicing defects. Of 4 unrelated patients with the XLT phenotype, 3 had missense mutations affecting exon 2 and 1 had a splice-site mutation affecting exon 9. Patients with classic WAS had more complex mutations, resulting in termination codons, frameshift, and early termination. These findings provide direct evidence that XLT and WAS are caused by mutations of the same gene and suggest that severe clinical phenotypes are associated with complex mutations.

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 Somatic mosaicism and compound heterozygosity in female hemophilia B

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1585-1587 ◽  
Author(s):  
Jean-Marc Costa ◽  
Dominique Vidaud ◽  
Ingrid Laurendeau ◽  
Michel Vidaud ◽  
Edith Fressinaud ◽  
...  
Keyword(s):  
Splice Site ◽  
Somatic Mosaicism ◽  
Splice Site Mutation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Hemorrhagic Diathesis ◽  
Site Mutation ◽  
History Of ◽  
Sporadic Cases ◽  
In Trans

Abstract Sequencing the complete factor IX gene of 2 sisters with hemophilia B with different phenotypes and no family history of hemorrhagic diathesis revealed a common 5′ splice site mutation in intron 3 (T6704C) in both and an additional missense mutation (I344T) in one. The presence of dysfunctional antigen in the latter strongly suggested that these mutations are in trans. Neither mutation was found in leukocyte DNA from the asymptomatic parents, but the mother was in somatic mosaicism for the shared splice site mutation. This case illustrates the importance of defining the phenotype and considering somatic mosaicism in sporadic cases. It underlines the limitations of complete gene sequencing for the detection of mosaicism and has implication for genetic counseling.

scholarly journals Somatic mosaicism and compound heterozygosity in female hemophilia B

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1585-1587
Author(s):  
Jean-Marc Costa ◽  
Dominique Vidaud ◽  
Ingrid Laurendeau ◽  
Michel Vidaud ◽  
Edith Fressinaud ◽  
...  
Keyword(s):  
Splice Site ◽  
Somatic Mosaicism ◽  
Splice Site Mutation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Hemorrhagic Diathesis ◽  
Site Mutation ◽  
History Of ◽  
Sporadic Cases ◽  
In Trans

Sequencing the complete factor IX gene of 2 sisters with hemophilia B with different phenotypes and no family history of hemorrhagic diathesis revealed a common 5′ splice site mutation in intron 3 (T6704C) in both and an additional missense mutation (I344T) in one. The presence of dysfunctional antigen in the latter strongly suggested that these mutations are in trans. Neither mutation was found in leukocyte DNA from the asymptomatic parents, but the mother was in somatic mosaicism for the shared splice site mutation. This case illustrates the importance of defining the phenotype and considering somatic mosaicism in sporadic cases. It underlines the limitations of complete gene sequencing for the detection of mosaicism and has implication for genetic counseling.

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.

Identification of Molecular Mutations Causing Haemophilia B From China: A Single-Center Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4627-4627
Author(s):  
Rong-Fu Zhou ◽  
Xian Zhang ◽  
Jian Ouyang ◽  
Yonggong Yang ◽  
Xiao-Yan Shao ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Cpg Islands ◽  
Gene Mutations ◽  
Splice Site Mutation ◽  
Hemophilia B ◽  
Missense Mutations ◽  
Site Mutation ◽  
Haemophilia B ◽  
Single Center Experience ◽  
Normal Plasma

Abstract Abstract 4627 Objective: To identify F9 gene mutations in patients with hemophilia B registered in Nanjing Drum Tower Hospital Hemophilia Registeration Center. Methods: One stage method was used to detect APTT, PT, TT, Fg and the activities of endogenous coagultation factors. Correction testing was employed to exclud the existence of inhibitor with mixed normal plasma. Genomic DNA was extracted from blood samples of 19 unrelated haemophilia B patients and their traceable family members. All exons and their flanking sequences of the F9 gene were amplificated by PCR and subsequently, the products were purified and sequenced directly. Results: APTT was significantly prolonged for all 19 cases of hemophilia B patients, but could be corrected by mixed normal plasma. According to the serial number, FIX:C was 3.7%, 3.5%, 1.9%, 1.9%, 2.2%, 2.0%, 1.9%, 3.2%, 3.5%, 10.8%, 7.8%, 2.2%, 3.8%, 2.3%, 1.6%, 1.4%, 3.7%, 7.8% and 3.5%, respectively. Thirteen different mutations of F9 gene were identified, including C 20518 T, T 6427 C, C 6460 T, C 31008 G, C 17761 T, A 17759 G, G 30150 A, G 31093 C, T 30930 C, G 20565 A, G 30987 A, A 6473 G and C 9 G, respectively. The mutations were composed of 10 missense mutations, one nonsense mutation, one a donor splice site mutation and one promoter mutation. Among them, mutations sites nt6460, nt17761, nt20518, nt30150 and nt31008 were located in CpG islands, belonging to mutation hot-spots. Mutations including C 9 G, C 31008 G and G 31093 C were firstly reported. Conclusions: No inhibitors are detected in the plasma of all patients. The F9 mutations are heterogenous and the missense mutations are the most prevalent gene defects in Chinese HB patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Frequent Occurrence of an Intron 4 Mutation in Multiple Endocrine Neoplasia Type 1

2002 ◽  
Vol 87 (6) ◽  
pp. 2688-2693 ◽  
Author(s):  
Jeremy J. O. Turner ◽  
Poloko D. Leotlela ◽  
Anna A. J. Pannett ◽  
Simon A. Forbes ◽  
J. H. Duncan Bassett ◽  
...  
Keyword(s):  
Splice Site ◽  
Splice Site Mutation ◽  
Pancreatic Tumors ◽  
Coding Region ◽  
Site Mutation ◽  
Autosomal Dominant Disorder ◽  
Acid Protein ◽  
Intron 4 ◽  
Amino Acid Protein

MEN1 is an autosomal dominant disorder characterized by parathyroid, pituitary, and pancreatic tumors. The MEN1 gene is located on chromosome 11q13 and encodes a 610-amino acid protein. MEN1 mutations are of diverse types and are scattered throughout the coding region, such that almost every MEN1 family will have its individual mutation. To further characterize such mutations we ascertained 34 unrelated MEN1 probands and undertook DNA sequence analysis. This identified 17 different mutations in 24 probands (2 nonsense, 2 missense, 2 in-frame deletions, 5 frameshift deletions, 1 frameshift deletional-insertion, 3 frameshift insertions, 1 donor splice site mutation, and a g→a transition that resulted in a novel acceptor splice site in intron 4). The intron 4 mutation was found in 7 unrelated families, and the tumors in these families varied considerably, indicating a lack of genotype-phenotype correlation. However, this intron 4 mutation is the most frequently occurring germline MEN1 mutation (∼10% of all mutations), and together with 5 others at codons 83–84, 118–119, 209–211, 418, and 516, accounts for 36.6% of all mutations, a finding that indicates an approach for identifying the widely diverse MEN1 mutations.

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