| A C-terminal amino acid substitution in the gamma-chain caused by a novel heterozygous frameshift mutation (Fibrinogen Matsumoto VII) results in hypofibrinogenaemia. | |
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MedLine Citation:
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PMID: 20589319 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We found a novel hypofibrinogenemia designated as Matsumoto VII (M-VII), which is caused by a heterozygous nucleotide deletion at position g.7651 in FGG and a subsequent frameshift mutation in codon 387 of the gamma-chain. This frameshift results in 25 amino acid substitutions, late termination of translation with elongation by 15 amino acids, and the introduction of a canonical glycosylation site. Western blot analysis of the patient's plasma fibrinogen visualised with anti-gamma-chain antibody revealed the presence of two extra bands. To identify the extra bands and determine which of the above-mentioned alterations caused the assembly and/or secretion defects in the patient, 11 variant vectors that introduced mutations into the cDNA of the gamma-chain or gamma'-chain were transfected into Chinese hamster ovary cells. In vitro expression of transfectants containing gammaDelta7651A and gammaDelta7651A/399T (gammaDelta7651A with an amino acid substitution of 399Asn by Thr and a variant lacking the canonical glycosylation site) demonstrated a reduction in secretion to approximately 20% of the level seen in the transfectants carrying the normal gamma-chain. Furthermore, results from other transfectants demonstrated that eight aberrant residues between 391 and 398 of the M-VII variant, rather than the 15 amino acid extension or the additional glycosylation, are responsible for the reduced levels of assembly and secretion of M-VII variant fibrinogen. Finally, the results of this study and our previous reports demonstrate that the fibrinogen gamma-chain C-terminal tail (388-411) is not necessary for protein assembly or secretion, but the aberrant amino acid sequence observed in the M-VII variant (especially 391-398) disturbs these functions. |
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Authors:
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Noriko Fujihara; Ayumi Haneishi; Kazuyoshi Yamauchi; Fumiko Terasawa; Toshiro Ito; Fumihiro Ishida; Nobuo Okumura |
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Publication Detail:
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Type: Case Reports; Journal Article; Research Support, Non-U.S. Gov't Date: 2010-06-29 |
Journal Detail:
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Title: Thrombosis and haemostasis Volume: 104 ISSN: 0340-6245 ISO Abbreviation: Thromb. Haemost. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-04 Completed Date: 2010-12-02 Revised Date: 2011-05-23 |
Medline Journal Info:
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Nlm Unique ID: 7608063 Medline TA: Thromb Haemost Country: Germany |
Other Details:
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Languages: eng Pagination: 213-23 Citation Subset: IM |
Affiliation:
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Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan. nobuoku@shinshu-u.ac.jp |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Afibrinogenemia
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blood,
genetics* Amino Acid Sequence Amino Acid Substitution* Animals Blood Coagulation / genetics* Blood Coagulation Tests Blotting, Western CHO Cells Cricetinae Cricetulus DNA Mutational Analysis Female Fibrinogens, Abnormal / genetics*, metabolism, secretion Frameshift Mutation* Genetic Predisposition to Disease Glycosylation Heterozygote* Humans Japan Middle Aged Molecular Sequence Data Phenotype Protein Multimerization Protein Processing, Post-Translational Protein Structure, Tertiary Transfection |
| Chemical | |
Reg. No./Substance:
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0/Fibrinogens, Abnormal; 0/fibrinogen Matsumoto VII |
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