A C-terminal amino acid substitution in the gamma-chain caused by a novel heterozygous frameshift mutation (Fibrinogen Matsumoto VII) results in hypofibrinogenemia
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概要
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This article is not an exact copy of the original published article in THROMBOSIS AND HAEMOSTASIS. The definitive publisher-authenticated version of Thrombosis and Haemostasis 2010 104 2: 213-223 is available online at: http://www.schattauer.de/de/magazine/uebersicht/zeitschriften-a-z/thrombosis-and-haemostasis.htmlWe 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 γ-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 visualized with anti-γ-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 γ-chain orγ’-chain were transfected into CHO cells. In vitro expression of transfectants containingγΔ7651A and γΔ7651A/399T (γΔ7651A 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 γ-chain. Furthermore, results from other transfectants demonstrated that 8 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 γ-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.
著者
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Terasawa Fumiko
Shinshu Univ. Jpn
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Terasawa Fumiko
Department Of Biomedical Laboratory Sciences School Of Health Sciences Shinshu University
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Okumura Nobuo
Shinshu Univ. Jpn
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Okumura Nobuo
Department Of Health And Medical Sciences Graduate School Of Medicine Shinshu University
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