The identification and classification of 41 novel mutations in the factor VIII gene (F8C)
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Abstract:
Hemophilia A is a bleeding disorder caused by a quantitative or qualitative deficiency in the coagulation factor VIII. Causative mutations are heterogeneous in nature and are distributed throughout the FVIII gene. With the exception of mutations that result in prematurely truncated protein, it has proved difficult to correlate mutation type/amino acid substitution with severity of disease. We have identified 81 mutations in 96 unrelated patients, all of whom have typed negative for the common IVS-22 inversion mutation. Forty-one of these mutations are not recorded on F8C gene mutation databases. We have analyzed these 41 mutations with regard to location, whether or not each is a cross-species conserved region, and type of substitution and correlated this information with the clinical severity of the disease. Our findings support the view that the phenotypic result of a mutation in the FVIII gene correlates more with the position of the amino acid change within the 3D structure of the protein than with the actual nature of the alteration.Keywords:
Amino acid substitution
Unstable hemoglobin (Hb) variants account for 9.5% of structural hemoglobinopathies. The majority of these unstable variants are the result of gene point mutations resulting in the substitution of a single amino acid by another. The presence of two mutations in the same allele is infrequent: of the 781 variants of the β-globin cluster described, only 32 are due to two point mutations (4.1%). Hb Extremadura is a structural variant that is included within the so-called unstable Hb anomalies. It was first described in 1989, employing the most up-to-date techniques available at that time, reversed phase high performance liquid chromatography (HPLC) to separate the abnormal chain (βX) digesting it with trypsin and analysis of the fragments with an automatic analyzer.
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Objective To detect parallelly the pattern of p53 gene point mutation from the paraffin specimen of hepatic cellular cancer(HCC).Methods Oligonucleotide chip which spoted 7 altofrequency mutation sites according to international data base of p53 gene mutation was designed,and p53 point mutation was detected with the technique of oligonucleotide chips.Results The frequency of p53 point mutation from the groups of HCC high and low occurrence were 64 3% and 14 3% respectively, P 0 05,and the main mutational form was 249ser (77 8%,among all mutation).Conclusions The point mutational hotspot of p53 gene from HCC high prevalent occurs at coding region 249(G T).Oligonucleotide chips can be applied to detect gene point mutation parallelly,high efficiently and at multipoint. China J Cancer Prev Treat,2003,10(5):452-454
Coding region
Mutation Testing
Mutation frequency
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We have completed the structural study of five rare types of inherited albumin variants (alloalbumins) discovered in the Biochemical Genetics Study of 15,581 unrelated children in Hiroshima and Nagasaki. We have also identified the structural change in five other alloalbumin specimens detected during clinical electrophoresis of sera from Japanese living near Tokyo. Each of the five albumin variants from Nagasaki and Hiroshima has a single amino acid substitution. All of these substitutions differ, and none has been reported in non-Japanese populations. No instances of proalbumin variants or of albumin B (the most frequent alloalbumins in Caucasians) were detected in the children in Hiroshima and Nagasaki. However, one instance of a variant proalbumin and two examples of albumin B occurred in Japanese from the vicinity of Tokyo. In addition a previously unreported point substitution was found in albumin Tochigi, which is present in two unrelated persons from Tochigi prefecture. Four of the point mutations in the Japanese alloalbumins are in close proximity in a short segment of the polypeptide chain (residues 354-382) in which three additional point substitutions have been reported in diverse populations. These results, combined with earlier data, suggest that point substitutions are grouped in certain segments of the albumin molecule.
Amino acid substitution
Serum Albumin
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To inquire into the molecular biological mechanisms of the occurrence of squamous cell carcinoma in eyes.Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, we detected 63 samples taken from 63 cases (including 36 invasive squamous carcinoma, 7 carcinoma in situ, 20 papillomas) for 248 point mutations in p53 gene.22.2% (8/36) squamous cell carcinomas, 14.3% (1/7) carcinomas in situ were shown to contain the point mutation in codon 248 of p53 gene exon 7 and no point mutation was found in papillomas, the difference being significant (P = 0.021). No point mutation was in patients over 70, while in patients younger than 70, the mutation rate was 33.3%, the difference being significant (P = 0.24). No significant correlation was found between p53 gene mutations and clinical pathological manifestations (P > 0.05).p53 gene mutations play roles in the early stage of the development of squamous cell carcinomas, and there is no correlation between p53 gene mutations and clinical manifestations. The mutation in p53 gene is not the main cause of neoplasms in the elder persons after the seventh decade of life.
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Objective To investigate the types and incidences of leukemia in Chinese children as well as the effects on etiology, the mutations of P53 gene was detetmined, Method Twenty-two DNA samples from Chinese children with leukemia were analysed by PCR-SSCP.The exon 4, 5, 6, 7, 8 of P53 gene were amplified respectively.The point mutations in these fragments were detected by SSCP.Results Nine of 22 children with leukemia existed heterozygous point mutations in P53 gene.Among all these exons, the relatively high incidence on exon 7 of 9 mutante somatio genes was revealed. Only 1of the 9 cases was germinal cell point mutation.Conclusions Like the solid-tumors,the P53 gene mutations can also be found extensively in the patients with leukemia.TLe inactivation of the gene is a very important factor in the cell malignant transformation.
Single-strand conformation polymorphism
genomic DNA
Malignant Transformation
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Human genetics
Genetic Code
Hemoglobin variants
Amino acid substitution
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Objective:To investigate the point mutation of p53 tumor suppressor gene in oral squamous cell carcinoma. Methods:Non-isotopic PCR-SSCP-EB staining technique was used in this study.Results:In 30 cases of oral squamous cell carcinoma samples, 16 point mutations of p53 gene were detected. Conclusion:The mutation rate of p53 gene in OSCC is 53.3%, and the point mutations of p53 gene are closely correlated with the tumorigenesis and development of oral squamous cell carcinoma. Compared with traditional technique, the non-isotopic PCR-SSCP-EB staining is a kind of simpler, safer, quicker and more effective way to detect the point mutation of p53 gene. [
Single-strand conformation polymorphism
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Mutational spectrum of p53 gene was analyzed by polymerase chain reaction (PCR)-single strand conformational polymorphism (SSCP) and direct DNA sequencing technique in tissue specimens of primary non-small cell lung cancer (NSCLC) to study the action of p53 gene, its type of mutations and its possible relation to different carcinogens. Results revealed that mutation of p53 gene was found in 94 of 128 resected specimens of NSCLC, including point mutations in 86 cases, deletion and insertion in seven and mutation of the linking site in one, and 63.9 percent of point mutations were G-T and T-G substitution and 25.6 percent G-A and A-G. It suggested that p53 gene mutation correlated closely to the occurrence of NSCLC. Possible environmental carcinogens were discussed in the paper based on the characteristics of the p53 gene mutation.
Single-strand conformation polymorphism
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Acknowledgments: This work was supported in part by office of Naval Research cooperative agreement # N‐00014‐96‐2‐0016 to the National Marrow Donor Program and by funding from the E.B. Foerderer Fund of the Children’s Hospital of Philadelphia to D.M. Abstract: The described alle HLA‐B*0811 is of Caucasoid origin. Most likely it derived from a point mutation of the B*0801 allele at position 559, where an adenine was converted to guanine. This position corresponds to codon 163 and resulted in an amino acid change from threonine to alanine. This substitution may influence both, T‐cell interactions and/or peptide binding ( Note ).
HLA-B
Amino acid substitution
Substitution (logic)
HLA-A
HLA-B Antigens
Alanine
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Non-isotopic PCR-SSCP technique was used to detect point mutation of p53 gene in fresh tissue taken from head and neck squamous cell carcinoma. The abnormal band of the single-stranded DNA (ssDNA) was identified in 7 of 13 cases. The results showed that point mutation occurred in the related DNA fragments. The point mutation of exon 5 was found in one case and that of exon 6, 7, 8 in two respectively. These results indicated that the p53 gene mutation was closely correlated with the development of head and neck squamous cell carcinoma. Compared with the traditional isotopic PCR-SSCP technique, the non-isotopic PCR-SSCP one is a kind of simpler, safer, quicker and more effective way to detect the mutation of p53 tumor suppressor gene. It is especially useful in the screening of point mutation when handling a large number of samples.
Single-strand conformation polymorphism
Epidermoid carcinoma
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